Antitussive and mucus regulating 2-substituted thiazolidines

ABSTRACT

2-Substituted thiazolidines compounds having formula I ##STR1## wherein X is a CH 2 , O or S, R is hydroxy or an acyloxy, alkyloxy, alkenyloxy or alkinyloxy group, R 1  is hydrogen or a group of formula ##STR2## R 2  is hydrogen or a free or esterified carboxy group, R a  and R b  are hydrogen or methyl, p is zero or 1, R 3  is hydrogen, a C 1  -C 2  alkylsulphonyl group, a phenyl or p-Cl phenyl, p-methylsulphonyl group or an acyl group; are useful as mucus regulating, antitussive and antibronchospastic agents.

This is a division of application Ser. No. 755,834 filed July 17, 1985now U.S. Pat. No. 4,798,898.

The present invention relates to antitussive and mucus regulating2-substituted thiazolidines, to process for their preparation and topharmaceutical and veterinary compositions containing them.

The compounds of the invention are 2-substituted thiazolidines of theformula (I): ##STR3## wherein: X is a CH₂, O, S;

R is hydroxy, or an ester thereof of formula R_(c) --CO₂ --, lower C₁-C₆ -alkoxy, CH₂ ═CH--CH₂ O--; HC.tbd.C--CH₂ --O--; methyl;

R₁ is hydrogen and ##STR4## R₂ is hydrogen or a free or esterifiedcarboxy group; R₃ is hydrogen, a C₁ -C₂ alkylsulphonyl group, anunsubstituted or mono or polysubstituted phenylsulfonyl group or an acylgroup of formul R_(d) CO;

p is zero or 1 with the proviso that when X is sulfur p is zero; bothR_(a) and R_(b), are hydrogen or methyl; Rc and Rd, which are the sameor different are: hydrogen, O--C(CH₃)₃, --(CH₂)_(n) --Q and ##STR5##wherein n is 0 or an integer from 1 to 7; P₁, P₂, are both hydrogen orone of them is hydrogen and the other one is lower C₁ -C₄ alkyl orphenyl and Q is selected in the group consisting of: hydrogen; a C₃ -C₄branched alkyl; a C₃ -C₇ cycloalkyl; free or esterified carboxy group;an halogen atom; SH; --NH₂ ; a mono or di-substituted amino, t-butoxycarbonylamino or C₁ -C₂ acylamino group; and ether --O--T or thioetherS-T chain, wherein T is an unsubstituted or mono- or polysubstitutedphenyl ring or a group of formula (CH₂)_(m) --T₁, wherein T₁ is selectedin the group consisting of H, OH, OCH₃, OC₂ H₅, HOCH₂ --CH₂ --, free andesterified carboxy group, NH₂, a C₁ -C₂ -acylamino or mono- ordisubstituted amino group, or a group of formula ##STR6## wherein R_(e)is hydrogen, methyl or ethyl and m is an integer from 1 to 3; a phenyl,phenoxy or phenylthio ring unsubstituted or mono- or polysubstituted inthe m, o, and p-positions; a group of formula --(CH₂)_(m)--SCO--(CH₂)_(n) P₃ wherein m and n have the above defined meanings andP₃ is a lower C₁ -C₇, linear or branched alkyl chain, a C₃ -C₆-cycloalkyl, a disubstituted aminogroup, a phenyl or phenoxy ring,optionally mono- or polysubstituted in the o, m and p-positions; analkenyl chain of formula ##STR7## wherein T, in addition to the abovedefined meanings, may also be hydrogen.

The term "mono substituted amino group" comprises, within the meaningsthereof, an amino group substituted by a C₁ -C₆, linear or branchedalkyl group or by groups having formula: --CH₂ --CH₂ --O--CH₂ --CH₃,--CH₂ --CH₂ --O--CH₂ --CH₂ --OH, --CH₂ --CH₂ --NH--CH₂ --CH₃, --CH₂--CH₂ --NH--CH₂ --CH₂ --OH or ##STR8##

The substituents of a disubstituted amino group according to theinvention may be linear or branched C₁ -C₆ alkyl groups or, takentogether, they represent an unsaturated or saturated nitrogen ring suchas morpholin-1-yl, pyrrolidin-1-yl, piperidin-1-yl,4-methyl-piperazin-1-yl, 4-ethyl-piperazin-1-yl,4-(2'-hydroxyethyl)piperazin-1-yl, 4-(4'-fluorophenyl)piperazin-1-yl;imidazol-1-yl, 3-pyridyl, 4-pyridyl.

Finally, the term "mono- or polysubstituted phenyl", according to theinvention, means phenyl groups which are substituted by a fluorine atomin the para position, by chlorine atoms in the meta and/or parapositionsor by a CF₃ in the meta positions or phenyl group of formula ##STR9##wherein Z₁ is H or COCH₃ and Z₂ is H, CH₃ or COCH₃ and P₄ is selected inthe group consisting of hydrogen, aminomethyl, C₁ -C₂ -acylaminomethylor mono- or di-substituted aminomethyl group, as above defined.

The optical antipodes, i.e. enantiomers, racemic mixtures thereof,diastereoisomers mixtures of compounds of formula I, have also to beconsidered as an object of the invention as well as non-toxic salts,both for pharmaceutical and veterinary use.

More particularly, the present invention relates to pharmaceuticallyacceptable base addition salts when in formula I a free carboxy group ispresent, and to pharmaceutically acceptable acid addition salts when informula I R₃ is hydrogen or an acyl grup in which is present a basicorganic moiety.

Typical examples of pharmacologically acceptable non-toxic bases areorganic bases e.g. organic amines such as methylamine, dimethylamine,trimethylamine, ethylamine, diisopropylamine, N-methyl-N-hexylamine,tromethamine, cyclohexylamine, N-methyl-N-cyclohexylamine,α-phenylethylamine, β-phenylethylamine, N,N-dimethylethanolamine,N,N-diethylethanolamine, ethylenediamine, piperidine, morpholine,piperidine, piperazine, galactamine, N-methylglucamine, ephedrine,lysine, arginine; and inorganic bases such as alkali and alkali-earthmetal hydroxydes as well as aluminium and zinc hydroxydes.

Typical examples of pharmacologically acceptable non-toxic acids areorganic acids such as acetic, formic, propionic, fumaric, maleic, malic,malonic, benzoic, salicylic, 3,4,5-trimethoxybenzoic, methanesulphonic,benzenesulphonic, canfosulphonic, lactic, aspartic, glutamic, L andD-2-phenyl-thiazolidin-5-carboxylic acid, cystin and cystein; andinorganic acids such as nitric, phosphoric, sulphoric, hydrochloric,hydrobromic acids.

Preferred salts of the invention comprise compounds of formula I whereinR₂ is a carboxy group salified with one of the above cited bases. Saltsof piperazine and imidazole derivatives are even more preferred.

In the formulae of this specification the wavy line bond ( ) indicatesthat the substituent has not a definite stereochemical identity, i.e.that the substituent may be both of (R) and (S) configuration; thebroken line ( ) indicates that a substituent is of (S) absolutestereochemistry; the heavy solid line ( ) indicates that a substituentis of (R) absolute configuration.

Particularly preferred compounds of the invention are those of formula Iwherein R₁, R_(a), R_(b) are hydrogen, X is an oxygen atom, R₃ is anacyl derivative.

Compounds of formula I wherein R is alkoxy, allyloxy, propargyloxy areparticularly preferred as antitussive agents.

Compounds of formula I wherein R is hydroxy and/or acyloxy areparticularly preferred as mucus regulating agents.

Specific examples of preferred compounds of the invention are thefollowing:

2-(O-methoxyphenoxy)methyl-3-acetylthioacetyl-thiazolidine;

2-(O-methoxyphenoxy)methyl-3-benzoylthioacetyl-thiazolidine;

2-(O-methoxyphenoxy)methyl-3-(3',4',5'-trimethoxy)-benzoylthioacetyl-thiazolidine;

2-(O-methoxyphenoxy)methyl-3-(4'-methyl-pyrazin-1-ylacetyl-thiazolidineand its di-hydrochloride salts;

2-(O-methoxyphenoxy)methyl-3-(4-methyl-pyrazin-1-yl)-acetyl-thioacetyl-thiazolidineand its bis hydrochloride salt;

2-(O-methoxyphenoxy)methyl-3-cyclopropylcarbonylthioacetyl-thiazolidine;

2-(O-methoxyphenoxy)methyl-3-(3'-cyclohexyl)propionylthioacetyl-thiazolidine;

2-(O-methoxyphenoxy)methyl-3-acetylthioacetyl-thiazolidine-sulfoxide;

2-(O-hydroxyphenoxy)methyl-3-ethoxyoxalyl-thiazolidine and itsmethylether;

2-(O-hydroxyphenoxy)methyl-3-cyclopropylcarbonyl-thiazolidine and itsmethylester;

2-(O-hydroxyphenoxy)methyl-3-imidazol-1'-yl-acetylthiazolidine and itsmethyl and ethylethers both as free base, as hydrochloride and nitratesalt;

2-(O-methoxyphenoxy)methyl-3-imidazol-1-yl-acetylthioacetyl-thiazolidineboth as free base or as nitrate salt;

2-(O-acetylthioacetoxy-phenoxy)methyl-3-acetylthioacetyl-thiazolidine;

2-[2'-(O-acetylthioacetoxyphenyl)ethyl]-3-acetylthioacetyl-thiazolidine;

2-(O-methoxyphenylthio)methyl-3-benzoylthioacetylthiazolidine;

2-(O-methoxyphenylthio)methyl-3-(4'-methylpiperazin-1'-yl)acetylthioacetyl-thiazolidine;

2-(O-methoxyphenylthio)methyl-3-(4'-methylpiperazin-1'-yl)acetyl-thioazolidineboth as free base and as di-hydrochloride salt;

2-[2'-(O-methoxyphenyl)ethyl]-3-benzoylthioacetyl-thiazolidine;

2-[2'-(O-methoxyphenyl)ethyl]-3-(4'-methyl-pyrazin-1-yl)acetyl-thiazolidine;

2-[2'-(O-methoxyphenyl)ethyl]-3-piperidin-1-yl-acetyl-thiazolidine;

2-(O-methoxyphenoxy)methyl-3-piperidin-1-yl-acetyl-thiazolidine;

2-(O-methoxyphenylthio)methyl-3-piperidin-1-yl-acetyl-thiazolidine;

3-(3'-morpholinomethyl-4'-hydroxy-3'-methoxy-cinnamoyl)-2-(O-methoxyphenoxy)-methyl-thiazolidine;

3-(3'-pyrrolidylmethyl-4'-hydroxy-3'-methoxy-cinnamoyl)-2-(O-hydroxyphenoxy)-methyl-thiazolidine;

3-[3-(2-hydroxyethylamino)ethylaminopropanoyl]-2-(O-methoxyphenoxy)methyl-thiazolidineand its maleate;

3-[3-(imidazol-1-yl)propionyl]-2-(O-methoxyphenoxy)methyl-thiazolidine;

3-(3,6-dioxa-capriloyl)-2-(O-methoxyphenoxy)methyl-thiazolidine;

3-(acetylaminoacetyl-2-(O-methoxyphenoxy)methyl-thiazolidine.

The compounds of the invention are prepared by reacting compounds offormula II ##STR10## wherein both W₁ and W₂ are a lower C₁ -C₂ alkoxyor, taken together, form a carbonyl group;

R' is a member selected from the group consisting of methyl, hydroxy, alower C₁ -C₆ alkoxy, allyloxy, propargyloxy;

X is a member selected from the group consisting of CH₂, S, O;

R₁ is hydrogen or ##STR11## where R' and X are as above defined, with anamino alkanethiol of formula III ##STR12## wherein R_(a), R_(b) and R₂have the above defined meanings, to give a compound of formula Ia##STR13## wherein R_(a), R_(b), R₂, R₁, R' and X are as above defined.

Compounds of formula I, wherein R₂ is hydrogen may be optionallysubjected to optical resolution; when R₂ is a free and/or an esterifiedcarboxy group, the single diastereoisomers and/or racemic mixtures ofthe diastereoisomers are optionally obtained.

Thiazolidines I and enantiomers or diastereoisomers thereof can beoptionally subjected to subsequent acylation by reaction with anacylating agent selected in the group consisting of:tert-butoxy-carbonate, a cyclic anhydride such as succinic and glutaricanhydride or an activated species of a carboxylic acid of the formulaeIVa and IVb or a sulphonyl halide of the formula IVc: ##STR14## wherein:Q, P₁, P₂ and n are as above defined;

R₄ is a C₁ -C₂ alkyl group, an unsubstituted or mono or polysubstitutedphenyl ring;

Hal is chlorine, bromine or iodine;

Z is a known species activating a carboxy group such as chlorine,bromine, azide, --O--CO--D where D is a C₁ -C₅ lower alkoxy andbenzyloxy, a C₁ -C₅ lower alkyl (mixed anhydride and anhydride) andactivated esters.

The obtained acyl-thiazolidines have the formula Ib ##STR15## wherein R,X, R_(a), R_(b), R₁ and R₂ have the above defined meanings and R'₃ is agroup of formula SO₂ --R₄ or CO--R_(d).

The acylation reaction can also be selectively carried out only on thethiazolidine nitrogen atom; in this case R can be an hydroxy atom.

By using in the acylation reaction a carbodiimide as activating speciesof the carboxy group, the acylation reaction can be optionally performedby reaction of a thiazolidine of formula I with an acid of the formulaIVa, IVb wherein Z is hydroxy.

Compounds Ib wherein X is different from S, can be optionally oxidizedby a suitable reagent to give compounds of formula Ic: ##STR16## whereinthe substituents have the above defined meanings.

Compounds of the general formula Id ##STR17## wherein R, R₁, R₂, R_(a),R_(b), p are as above defined and at least one of P₁ or P₂ is hydrogenand the other is hydrogen, methyl or phenyl, Q' is an halogen atom and nis preferably zero, may be optionally reacted with a salt of athiocarboxylic acid of the formula:

    P.sub.3 --(CH.sub.2).sub.n --CO--S.sup.(-) Base.sup.(+)

wherein P₃ is as above defined and the base is selected in the groupconsisting of sodium, potassium, magnesium, calcium, lowertrialkylammonium, phenyldialkylammonium, to give the compounds offormula Id in two steps wherein Q' is P₃ --(CH₂)_(n) --CO--S; theselatter compounds can be optionally reacted with ammonia, too, to give acompounds of formula Id wherein Q' is a free thiolyl group from whichcompounds of formula Id wherein Q' is an alkylthioeter group, can beoptionally obtained by reaction with an alkyl halide in the presence ofa base.

Finally, the compounds of formula Id wherein n is zero, P₁ and P₂ arehydrogen and Q' is Cl, Br or I may optionally be reacted withtriphenylphosphine in an inert solvent (benzene, acetonitrile, THFetc.): the obtained phosphonium salt is optionally converted into astabilized ylide compound of the formula Ie: ##STR18## wherein R, R_(a),R_(b), R₁, R₂ and p are as above defined, with an aldehyde of theformula (V)

    T--CHO                                                     (V)

wherein T is also as above defined, to give, after optional removal ofthe protective groups, 3-thiazolidine acrylamides of the formula If##STR19## which, when T is H, C₁ -C₄ -lower alkyl and phenyl, can beoptionally reacted with nucleophiles such as amines (i.e. H₂N--(CH₂)_(m) --T₁, monosubstituted and disubstituted amines) and thiols(i.e.: HS--(CH₂)_(m) --T₁, unsubstituted or mono or polysubstitutedthiophenols) to obtain a Michael adduct of formula (Ig) ##STR20##wherein R, R₁, R_(a), R_(b), R₂, p, x are as above defined and Q' isselected in the group consisting of HN--(CH₂)_(m) --T₁, mono anddisubstituted amino group, S--(CH₂)_(n) --T₁ (m, n and T₁ are as abovedefined) unsubstituted, mono or polysubstituted phenylthio group and nis 1.

When in the above general formulae Ib-Id R represents an esterifiedhydroxy group (R_(c) CO₂ --), the protective ester group can beselectively removed and the resulting hydroxy group may be optionallysubjected to selective esterification.

The cyclization of a compound of formula II with an aminealkanethiol offormula III to form a 2-substituted thiazolidine ring may be performedby reaction with either a stoichiometric amount or a small excess of theamine alkanethiol in an aqueous solvent, either in the presence orabsence of a catalytic amount of its ammonium salt such as acetate,formiate, canfosulfonate, hydrochloride.

Suitable solvents are, for example, water, methanol, ethanol, aceticacid and mixtures thereof.

The reaction is preferably carried out at temperatures ranging fromabout -20° C. to the solvent's reflux temperature; preferably thereaction is performed at room temperature.

The reaction times range from few minutes to several days, but usuallythey do not exceed two hours and often a few minutes are sufficient tocomplete the reaction.

The optical resolution of the compounds of formula Ia may be optionallycarried out by salification with an optically active acid such as forexample d- and 1-canfosulphonic acid, d- and 1-lactic acid, d- and1-mandelic acid, d- and1-6-exo-chloro-7-syncarboxy-bicyclo[2,2,1]-heptan-3-one-3,3-ethylendioxyfollowed by crystallization till constant rotatory power and recovery ofthe optionally active 2-substituted-thiazolidine.

Suitable solvents are, for example, alcohols such as methanol, ethanol,1-propanol, 2-propanol, ethers such as ethylether, isopropylether,dioxane, tetrahydrofuran, esters such as ethylformiate and ethylacetateand hydrocarbons such as benzene, toluene, cyclohexane, hexane andmixtures thereof.

The optical resolution is preferably carried out at room temperature andfew crystallizations are generally necessary to obtain a constantrotatory power.

The optional acylation of the compounds of formula Ia with an acylatingagent of formula IV may be performed by reaction with either astoichiometric amount or a small excess of acylating agent in an inertsolvent in the presence of either a stoichiometric amount or of anexcess of a base. Suitable solvents are, for example, halogenatedhydrocarbons such as CH₂ Cl₂, CHCl₃, Cl--CH₂ CH₂ Cl; ketones such asacetone and butan-2-one; hydrocarbons such as hexane, cyclohexane,benzene, toluene, pyridine and mixtures thereof.

A nearly stoichiometric amount of base for any molecule of the acylatingagent is useful. Such a base may be an inorganic base e.g. an alkali oran alkali-earth metal oxide, carbonate or bicarbonate, e.g. CaO, CaCO₃,K₂ CO₃, KHCO₃, Na₂ CO₃, NaHCO₃ ; an organic base such as a tertiaryamine, e.g. trimethylamine, tributylamine; or an aromatic base, e.g.pyridine, an alkyl substituted pyridine, a N,N-dialkyl-aniline; or ananionic ion-exchange resin.

The acylation reaction is preferably carried out at temperatures rangingfrom about -40° to about the solvent's reflux temperature; preferablythe reaction is performed at room temperature.

A temperature below 0° C, ranging from -40° to about -50° may bepreferably used when a free phenolic group is also present and anequivalent of the acylating agent is used in order to obtain theoptional acylation of the thiazolidine ring without affecting thephenolic group.

Using in the acylation reaction, a carboxylic acid of formula IVa andIVb (Z═OH), the reaction is performed in the presence of an excess of acondensating agent, such as a carbodiimide and preferablydicyclohexylcarbodiimide, in an inert solvent, at room temperature, inthe presence or absence of catalytic amounts of 4-dimethylaminopyridine.

The optional oxidation of the compounds of formula Ib to obtain athiazolidine sulphoxide of formula Ic may be performed by reaction witheither a stoichiometric amount or a small excess of an organic peracidsuch as monoperphtalic acid, m-chloroperbenzoic, peracetic acid,performic acid and perbenzoic acid in an inert solvent either in thepresence or in the absence of a base.

Preferred oxidizing agent is a stoichiometric amount of monoperphtalicacid, the preferred solvent is ethyl acetate and the reaction ispreferably performed in the presence of an excess of NaHCO₃.

The oxidation reaction is preferably carried out at temperature rangingfrom about -25° C. to room temperature; preferably the reaction isperformed at 0° C.

The thiolation of a compound of formula Id wherein Q' is a halogen atommay be optionally performed by treatment with either a stoichiometricamount or an excess of a salt of a thiocarboxylic acid and/or ofthiophenol acid such as for example, sodium, potassium salt and/or "insitu" formed salt of the thiocarboxylic acid with a generic organic basesuch as trimethylamine, triethylamine, tributylamine, in an inertsolvent.

Suitable solvents are, for example, halogenated hydrocarbons, ketones,esters, ethers, alcohols and the mixtures thereof.

The reaction is preferably carried out at room temperature and thereaction times range from few minutes to several hours but, usually, thereaction times do not exceed two hours at room temperature.

A free thiol group may by optionally obtained reacting the thioacylcompounds with an excess of aqueous ammonia solution in inert gasatmosphere at room temperature.

The reaction is optionally performed at room temperature, suitablesolvents are alcohols such as methanol, ethanol, glycols and ethersmiscible with aqueous ammonia solutions such as dimethoxyethane,dioxane, tetrahydrofurane and mixtures thereof.

The optional acylation of the free thiol and phenolic group may beperformed as above described.

The optional alkylation of the free thiol group may be performed bytreatment of the potassium and/or sodium salt of the thiol compound withan alkyl halide.

The reaction between the stabilized ylides of the formula Ie and thealdehydes of formula V is the well-known Witting reaction whoseexperimental procedure is also well-known; it is generally performed bymixing the reagents is equimolecular ratio in an inert solvent such asan halogenated solvent, an ethereal solvent (THF, dimethoxyethane,etc.), hydrocarbons (cyclohexane, benzene, toluene, hexane),acetonitrile or using a mixture thereof, preferably at room temperature.

The Michael addition of the above defined nucleophiles to theacrylamides of the formula Ia is also a well-known reaction. Preferredsolvents are alcohols and the reaction is carried out by mixing thereagent and heating at the reflux temperature.

The thiazolidines of formula I wherein R is hydroxy and R₃ is --CO₂C(CH₃)₃ may be optionally reacted with a lower C₁ -C₆ -alkyl halide, apropargyl halide and allylhalide in an aprotic solvent such asdimethylformamide in the presence of potassium carbonate to give acompound of formula I wherein R is a lower C₁ -C₆ alkoxy, CH₂ ═CH--CH₂--O-- and HC.tbd.CH--CH₂ O.

The subsequent optional cleavage with trifluoroacetic acid of theprotective tert-butoxy-carbonyl group affords the correspondingthiazolidines of formula I, wherein R is a lower C₁ -C₆ alkoxy, allyloxyand propargyloxy and R₁ is hydrogen.

The compounds of formula II are known compounds or may be prepared byknown methods.

Particularly 2- -hydroxy-3,4-dihydroxy-benzopyrane, and 2--hydroxy-1,4-benzodioxane are optionally prepared by reduction withDIBAH of the corresponding lactones i.e. 3,4-dihydro-benzopyran-2-one(dihydrocoumarin) and 1,4-benzodioxan-2-one.

Also the amine alkanethiol of formula III, the acylating agents offormula IV and the thiocarboxylic acids and the aldehydes of formula Vare known compounds or may be prepared by known methods.

The compounds of the invention are therapeutically active substances,devoid of acute, subacute or chronic toxic effects, suitable for use asantitussive agents and mucus regulating agents.

In fact for example the compounds of the invention never exhibit acutetoxic effects in mice and rats.

LD₅₀ values above 1 g/kg are generally determined both after oral andintraperitoneal administration of the compounds of the invention.

The compound4-carboethoxy-3-acetylthioacetyl-2-(o-methoxyphenoxy)methyl-thiazolidinediffers from the other ones, because it shows in mice LD₅₀ such as 0,76g/kg (os) and 0.67 g/kg (i.p.). A sedative effect, starting from 30mg/kg, is also present.

The techniques described by Charlier et al. (Arch. Int. Pharmacodyn.134, 306, 1961) and by Stefko et al. (J. Pharm. Exp. Therap., 108, 217,1953), adapted with minor modifications, are used to investigate theantitussive properties of the compounds of the invention. Codeinephosphate is used as positive reference compound.

According to the Charlier procedure guinea pigs are exposed to a citricacid aerosol (7.5%) and cough is recorded 60 minutes after theantitussive treatment by i.p. route. Male animals of 300-400 g pigs areplaced in a perspex box (20×30×30 cm) connected to an aerosolcompressor; the animals are subjected to a citric acid saturatedatmosphere, 60 minutes after the i.p. injection of a compound of theinvention (0.1 and 0.3M solutions; 1 ml/kg).

The total number of cough strokes and the delay of the first cough arerecorded during the first five minutes.

Five guinea pigs are used for each dose level and the results arecompared with controls (vehicle treatment) and codeine phosphate 0.07Msolution (standard treatment).

ED₅₀ and the corresponding delay of first cough stroke are calculated.

The data obtained by i.p. administration are confirmed by oraladministration.

In the Stefko procedure, conscious mongrel dogs (15±3 kg body weight)are used; the compounds of the invention are tested for their ability toinhibit cough induced by electric stimulation.

Under general anesthesia, two insulated nichrome wires (0.4 mm diameter)are surgically implanted into the submucosa of the trachea.

About two days later, the dogs are placed in a sling and theexteriorized electrodes are connected to an electric stimulating device(such as Grass S 48 Mod.).

The stimulation parameters such as: delay 0.01 msec, duration 1 msec,frequency 30 Hz, are used.

An electrical stimulus of 1 sec is applied 10 times at 5 sec intervalsin order to determine the minimum voltage necessary for elicitingreproducible cough response. Then, tussive responses to the electricalstimuli are registered at 15, 30, 60, 90, 120, 150, 180, 240, 300 and360 minutes after oral administration of the compounds of the invention.

The tussive responses are scored as follows: 1: no response; 2: sigh orexaggerated expiration; 3: marked cough; 4: one marked cough and oneexaggerated expiration: 5: two marked coughs.

Six dogs are employed for each determination and the mean activity iscalculated.

The inhibition percent of the cough response and the duration ofactivity are compared with codeine.

In the guinea pig cough test, codeine phosphate shows an ED₅₀ ≃23 mg/kgwith a 170% delay

In the dog cough test, codeine phosphate when tested at 8 mg/kg shows a52% inhibition of the cough stimulus for a long time (about 2-4 hours).

The mucus regulating properties of the compounds of the invention areinvestigated "in vivo" by means of experiments carried out on male NewZealand white rabbits. The animals are submitted to inhalation of a 5%H₂ SO₃ aqueous solution by aerosol (exposition of 3 hours a day for 3alternate days), to induce a chronic bronchial inflammatory diseasewhich causes a production of pathological sputum in the bronchial tree.

Aim of the experiments is to evaluate modifications of selectiveparameters such as dry weight of the sputum, viscosity, content inproteins, phospholipids, galactose, sialic acid and fucose, induced inthis pathological sputum by pharmacological treatment with the compoundsof the invention.

To this purpose, the sputum produced in the bronchial tree is collecteddaily, through a "T" shaped glass cannula, inserted in the trachea,before and after oral twice a day (9.00 a.m. and 4.00 p.m.) treatmentwith one of the compounds of the invention.

The schedule treatment procedure is shown in the following Scheme 1:##STR21## where 0 indicates the day of implantation of the trachealcannula; -7-5-3 indicate the days of H₂ SO₃ treatment (H); 1,2,3,4indicate the days of oral administration of the compounds of theinvention (T) and the time of mucus collection (M).

The mucus collected in day 1 in the morning is considered as a blank; 7indicates the day of the animal sacrifice after the mucus collection.

The sputum samples are stored in the freezer (-20° C.) until theinvestigation of biological and rheological parameters is carried out.

The samples are investigated for relative viscosity, measured at 37° C.with a Brookfield viscometer (model LT VD) equipped with a 1,565°cone-plate, and aliquoted for biochemical analysis of protein,phospholipids, galactose, sialic acid and fucose contents. Dry weight ofthe mucus is also determined. For each parameter, cumulative data arereferred to a seven days period after the beginning of the treatment andthey are extrapolated using the AUC method (area under curve) calculatedby the trapezoidal rule. Finally the data are compared with dataobtained from controls (vehicle treatment), non bronchitic rabbits(vehicle treatment) and positive controls bronchitis rabbits treatedwith 0.153M 2-carboxymethyl cysteine.

In Table 1 the AUC values, determined for the various parameters, afterthe treatment of bronchitic rabbits with S-carboxymethyl cysteine arereported.

                                      TABLE I                                     __________________________________________________________________________    AUC as a % compared to bronchitic controls                                               Mucus                  Sialic                                            Viscosity                                                                          production                                                                          Protein                                                                           Phospholipids                                                                        Galactose                                                                           acid                                                                              Fucose                                  Treatment                                                                           (cps)                                                                              ml/kg mg/ml                                                                             mg/ml  mg/ml mg/ml                                                                             mg/ml                                   __________________________________________________________________________    Controls                                                                            100  100   100 100    100   100 100                                     S--carboxy-                                                                   methyl cy-                                                                          52   97    105 108    64    60  56                                      steine                                                                        0.153 M                                                                       __________________________________________________________________________

As it is evident, all the parameters are influenced by thepharmacological treatment with S-carboxymethyl cysteine.

An ideal mucoregulating agent should reduce the viscosity and theprotein content of the mucus.

In pathological cases, the high protein content of the mucus could berelated to an abnormal production of the mucus macromolecules and alsoto an abnormal passive transport of seric proteins through the capillaryvessels.

At the same time, the reduction of the mucoprotein content should beassociated with a reduction of the contents of galactose and sialic acidin the sputum, so indicating a lower tendency to produce mucines whichcontribute to the viscosity of the mucus.

Fucose content is related to the production of neutral mucines.

The increase in the mucus volume is connected to a reparative localprocess for which a liquefation of the mucus is obtained. This event isparticularly desirable when, as in some pathological conditions, themucus of the patients appears to be adhesive and highly viscous, socontributing to the obstruction of the respiratory ways.

The results obtained with some compounds of the invention, administeredorally in equimolecular amounts in comparison with the standardS-carboxymethyl cysteine, are shown in Table 2.

                                      TABLE 2                                     __________________________________________________________________________    AUC as a 100% compared to bronchitic controls                                                  Mucus                  Sialic                                            Viscosity                                                                          production                                                                          Protein                                                                           Phospholipids                                                                        Galactose                                                                           acid Fucose                           Treatment   (cps)                                                                              (ml/kg)                                                                             (mg/ml)                                                                           (mg/ml)                                                                              (mg/ml)                                                                             (mg/ml)                                                                            (mg/ml)                          __________________________________________________________________________    animal untreated with                                                                     90   72    96  79     30    78   85                               H.sub.2 SO.sub.3                                                              bronchitic animal                                                                         100  100   100 100    100   100  100                              (5% H.sub.2 SO.sub.3 aerosol                                                  2-(o-methoxyphenoxy)-                                                                     116  124   92  106    59    85   76                               methyl-thiazolidine                                                           2-(o-methoxyphenoxy)-                                                                     40   95    48  49     29    52   55                               methyl-thiazolidine-4-                                                        carboxy                                                                       2-(o-methoxyphenoxy)-                                                                     59   127   78  37     57    107  151                              methyl-thiazolidine-3-                                                        acetyl-thioacetyl                                                             2-(o-methoxyphenoxy)-                                                                     91   65    79  102    69    78   111                              methyl-thiazolidine-                                                          3-acetylthioacetyl-                                                           4-carbethoxy                                                                  2-(o-methoxyphenoxy)-                                                                     65.1 108.7 62  59.8   52.3  56.8 149.3                            methyl-3-(ethoxyoxa-                                                          lyl)-thiazolidine                                                             2-(o-methoxyphenoxy)-                                                                     92.6 90    57.9                                                                              74.5   60.0  60   103.6                            methyl-3-cyclopropyl-                                                         carbonyl-thiazolidine                                                         2-(o-acetylthioacetoxy-                                                                   71.9 74.0  46.9                                                                              49.8   72.9  31.3 147.9                            phenoxy)methyl-3-ace-                                                         tylthioacetyl-thiazoli-                                                       dine                                                                          2-(o-methoxyphenoxy)-                                                                     39.1 162.5 55.2                                                                              65.8   21.8  63.8 97.5                             methyl-3-(2'-imidazol-                                                        1"'-yl)acetyl-thiazo-                                                         lidine                                                                        2-(o-hydroxyphenoxy)-                                                                     31.9 99.2  62.0                                                                              47     38.2  49.5 90.8                             methyl-3-acetylthio-                                                          acetyl-thiazolidine                                                           2-[2'-(o-acetylthioace-                                                                   70   76.1  48  47.2   67    36.2 128                              toxyphenoxy)methyl]-3-                                                        acetylthioacetyl-thi -a                                                       zolidine                                                                      __________________________________________________________________________

3-Acetylthioacetyl-2-(o-methoxyphenoxymethyl)thiazolidine is a typicalcompound of the invention having mucus regulating properties as well asgood antitussive activity.

The compound shows an ED₅₀ lower than 5 mg/kg (185% delay) in the guineapig cough test. At doses of 20 mg/kg, this acetylthiothiazolidinecompound shows a 54.2% inhibition of the cough stimulus in the dog alsoexhibiting a more favourable duration of action in comparison tocodeine.

Other compounds of the invention such as:3-benzoylthioacetyl-2-(o-methoxyphenoxy)methylthiazolidine;3-(3'-cyclohexyl)propionylthioacetyl-2-(o-methoxyphenoxy)methylthiazolidine;3-(4'-methyl-piperazin-1'-yl)acetylthioacetyl-2-(o-methoxyphenoxy)methylthiazolidine·2 HCl;3-(4'-methylpiperazin-1'-yl)acetyl-2-(o-methoxyphenoxy)methylthiazolidine.multidot.2HCl; 3-acetylthioacetyl-2-(o-methoxyphenylthio)methylthiazolidine, and3-acetylthioacetyl-2-[2'-(o-methoxy-phenyl)ethyl]-methyl-thiazolidineexhibit in the guinea pig cough test ED₅₀ ranging from 0.5 to 4 mg/kgwith a % delay of the first cough (control 100) also ranging from 135 to316%.

The guinea pig cough test and the dog cough test are effective andreliable testing procedures for the screening of substances useful inthe treatment of cough of different origines and in the relief of thepain induced by tussive attacks.

Accordingly, the compounds of the invention may be useful in thetreatment of patients in order to reduce and to prevent tussive attacks.Therefore the compounds of the invention are also useful to stopparoxysm of coughing which could precipitate syncope.

Prevention and stopping strenuous coughing is also highly useful becausecought may produce rupture of an emphysematous bled and rib fractures.

Although cough fractures of the ribs may occur in otherwise normalpatients, their occurrence should at least raise the possibility ofpathologic fractures, which are seen in multiple myeloma, osteoporosisand osteolytic metastase.

Particularly preferred compounds of the invention as antitussive agentsare compounds like3-(acylthioacetyl)-2-(o-methoxyphenoxy)methylthiazolidine and/or3-(methylpiperazinacetyl)-2-(o-methoxyphenoxy)methylthiazolidine and/or3-(methylpiperazinoacetylthioacetyl)-2-(o-methoxyphenoxy)methylthiazolidine.Further preferred compounds are their 2-(o-methoxyphenylthio)methyl- andtheir 2-[2'-(p-methoxyphenyl)ethyl]analogues which are endowed with astrong antitussive property together with a comparatively faible mucusregulator activity.

A decrease of the antitussive potency together with a favourableincrease of the mucus regulating ability is surprisingly noted, when incompounds 1 the alkoxy, allyloxy and propargyloxy groups of R aresubstituted by a hydroxy or an acyloxy group, as it can be noticed, forexample, from the data reported in Table 2, particularly for thecompounds 2, 9, 7, 10.

In the guinea pig cough test, the compounds 9, 7, 10 exhibit ED₅₀ valuessuch as 60, 162 and 61 mg/kg, respectively, indicating an almost 10times decrease of the antitussive potency in comparison with thereference compound 3 (ED₅₀ ≃5 mg/kg). To this decrease of potency asantitussive agents corresponds a particularly favourable increase oftheir mucus regulating activity.

These latter data provide also evidence that a changing in X, i.e. amethylene group instead of oxygen, increases the antitussive potency.

In Table 3 some data reported relating to the antitussive properties ofsome 4-carboxy-thiazolidines of the invention.

                                      TABLE 3                                     __________________________________________________________________________                          Dog cough test                                                   Guinea pig cough test                                                                      % inhibition                                                                           duration                                       Compound ED.sub.50 (mg/kg)                                                                     % delay                                                                            of cough stimulus                                                                      of action                                      __________________________________________________________________________    2-(o-methoxy-                                                                 phenoxy)methyl-                                                               4-carboxythia-                                                                         inactive                                                                              --   43.8     middle                                         zolidine                                                                      2-(o-methoxy-                                                                 phenoxy)methyl-                                                               4-carbethoxythia-                                                                      inactive                                                                              --   26.7     short                                          zolidine                                                                      2-(o-methoxy-                                                                 phenoxy)methyl-                                                               3-acetylthioace-                                                                       77.1    350  --       --                                             tylthiazolidine                                                               __________________________________________________________________________

On the other hand, compounds such as 3-(ethoxyoxalyl)- and3-(cyclopropyl)carboxyl-2-(o-methoxyphenoxy)methylthiazolidine appear tobe devoid of any antitussive properties both in the guinea pig and dogcough tests.3-(Imidazol-1'-yl)acetyl-2-(o-methoxyphenoxy)methylthiazolidine and its2-(o-hydroxyphenoxy)methyl-analogue display a reduced antitussivepotency (ED₅₀ 40.6 mg/kg and 96 mg/kg respectively, while retaining astrong mucus regulating activity (see table 1)).

This graduality in antitussive potency together with a very high mucusregulating activity is highly desirable in some pathological conditionssuch as chronic bronchitis, in which it is not always desirable tosuppress a cough productive of significant quantities of sputum. In somecases, an early suppression of the cough could mean ritention of themucus in the tracheobronchial tree, negative interference with thedistribution of the ventilation alveolar aeration and with the abilityof the lung to resist infections.

The changes induced in the mucus by the treatment with selective mucusregulators as a consequence may reduce the number of cough attacks.

In accordance with this aim particularly useful and preferred substanceswhich exhibit a high mucus regulating activity together with a reducedantitussive potency are2-(o-hydroxyphenoxy)methyl-4-carboxy-thiazolidine,2-(o-hydroxyphenoxy)methyl-thiazolidines 3-substituted with3-alkoxyoxalyl, 3-cyclopropylcarbonyl-, 3-(imidazol-1-yl)acetyl,3-(3',4'-dihydroxy)cinnamoyl, 3-(3'-methoxy-4'-hydroxy)cinnamoyl groups.

Bis-2-(o-methoxyphenoxy)methyl-thiazolidines such as the3-acetylthioacetyl and the 4-carboethoxy derivatives show alsoantitussive properties with ED₅₀ values of 230 and 116 mg/kgrespectively. The 3-acetylthio compound is also active in the dog coughtest (13% inhibition of the cough stimulus) in which it shows a veryprolonged action (2-3 times longer than that of codeine phosphate).

In contrast to the2-(o-methoxyphenoxy)methyl-3-acetylthioacetylthiazolidine, its2-(o-tolyloxy)methyl analogue is devoid of any antitussive properties.In addition, when tested as mucus regulator, it increases viscosity,protein and fucose content in the mucus, poorly affecting galactose andsialic content. Also2-tolyloxy-methyl-3-(imidazol-1'-yl)acetylthiazolidine is not active inthe cough tests, exhibiting some mucusregulating action in thebronchitic rabbits, with a spectrum of action very close to that ofcarboxymethylcysteine.

Some compounds of the invention display also a protecting action on theliver of mice against paracetamol and CCl₄ poisoning.

The compounds3-[(3,6-dioxa-capriloyl)-2-(O-methoxyphenoxy)-methyl-thiazolidine,3-(3-thia-6-oxacapriloyl)-2-(O-methoxyphenoxy)-methyl-thiazolidine,3-(3-imidazolyl-propionyl)-2-(O-methoxyphenoxy)-methyl-thiazolidine,3-(3'-imidazol-1-yl)-propionyl-2-(O-propargyloxyphenoxymethyl)-thiazolidine,when tested to a dosage level 0.01-0.08M, are mucus regulating agents atleast as effective as 0.153M of 5-carboxymethylcysteine.

Moreover, the compounds3-(acetylglicinyl)-2-(0-methoxyphenoxy)-methyl-thiazolidine,3-BOC-2-(O-methoxyphenoxy)-methyl-thiazolidine,3-glicinyl-2-(O-methoxyphenoxy)-methyl-thiazolidine and its2-(O-allyloxyphenoxy)-methyl analogue are also endowed with goodantitussive properties with ED₅₀ ranging from 3 to 30 mg/kg.

The compounds3-[3-(2-(2-hydroxyethylamino)ethylamino)propionyl)]-2-(O-methoxyphenoxy)-methyl-thiazolidinemaleate and its 2-O-propargyloxy analogue are also particularlyeffective as antitussive agents with an ED₅₀ ranging from 3 to 6 mg/kgand are both characterized by a very prolonged duration of action.

The compounds of the invention are also characterized by a pronouncedability to induce relaxation of the bronchial and tracheal smoothmuscle.

For instance,3-(3'-morpholinomethyl-4'-hydroxy-5'-methoxy-cinnamoyl)-2-(O-methoxyphenoxy)-methyl-thiazolidine.HClis able to relaxe "in vitro" guinea pig trachea smooth muscle stripscontracted by methacoline with ED₅₀ of 1.9×10⁻⁴ M. The spasmolyticactivity of the new substance favourably compares with that ofdihydroxypropyltheophylline (ED₅₀ 0.76×10⁻⁴ M). After intrajugularadministration; the compound appears 3-6 times more active thanaminophylline in the resolution of bronchospasm induced by i.v.histamine in anesthetized guinea-pigs (Konzett-Ressler test).

Therefore, compounds I are effective antitussive, bronchodilating andmucus regulating agents. They may be administered by oral, sublingual,intravenous, subcutaneous, intramuscular, rectal or inhalatory route.

The inhalatory route is particularly preferred when a mucus regulatingaction is requested.

The preferred doses of the compounds range from 0.05 to about 5mg/kg/day, according to the patient's conditions, weight, age, andadministration route.

The preferred doses by inhalatory route range from 0.05 to 1 mg/kg/day.

As previously stated, the compounds of the invention can be administeredeither to humans or animals in a variety of dosage forms, e.g., orallyin the form of tablets, capsules, or liquids; rectally, in the form ofsuppositories; parenterally, subcutaneously of intramuscularly, withintravenous administration being preferred in emergency situations; byinhalation in the form of aerosols or solutions for nebulizers; in theform of sterile implants for prolonged action. The pharmaceutical orveterinary compositions containing the compounds of the invention may beprepared in conventional ways and contain conventional carriers and/ordiluents.

For example, for intravenous injection or infusion, sterile aqueousisotonic solutions are preferred. For subcutaneous or intramuscularinjection, sterile solutions or suspensions in aqueous or non-aqueousmedia may be used; for tissue implants, a sterile tablet or siliconerubber capsule, containing or impregnated with the compound is used.

Conventional carriers or diluents are, for example, water, gelatine,lactose, dextrose, saccharose, mannitol, sorbitol, cellulose, talc,stearic acid, calcium or magnesium stearate, glycol, starch, arabic gum,tragacanth gum, alginic acid or alginates, lecithin, polysorbate,vegetable oils, etc.

For administration by nebulizer, a suspension or a solution of thecompound of the invention, preferably in the form of a salt, such as thesodium salt in water (and/or the nitrate salt) can be used.Alternatively, the pharmaceutical preparation can be in the form of asuspension or of a solution of the compound of the invention in one ofthe usual liquefied propellants, such as dichlorodifluoromethane ordichlorotetrafluoroethane, administered from a pressurized containersuch as an aerosol bomb. When the compound is not soluble in thepropellant it may be necessary to add a co-solvent, such as ethanol,dipropylene glycol and/or a surfactant to the pharmaceuticalformulation.

The following examples illustrate but do not limit the presentinvention.

EXAMPLE 1

A solution of potassium hydroxide (8.46 g) in 2-propanol and water (3ml) is added to a mixture of pyrocathechine monomethyl ether (28.5 g)and epichlorohydrin (10 ml) in 2-propanol (320 ml). The mixture isheated to reflux for 2 hours, the excess of the solvent is distilled outand the residue is poured in ice-water. The precipitate is filtered andcrystallized from isopropylether to give1,3-di-o-methoxyphenoxypropan-2-ol (28.8 g); m.p. 73°-75°.

A solution of this compound in dry benzene-DMSO (3:1, 250 ml) is treatedwith dicyclohexylcarbodiimide (55 g), pyridine (8 ml) andtrifluoroacetic acid (4 ml). The mixture is stirred for 3 hours at roomtemperature, then the excess of reagent is destroyed by cautiousaddition of a solution of oxalic acid (10 g) in methanol (20 ml). Themixture is diluted with water (150 ml) and filtered to remove theprecipitated dicyclohexylurea. The organic phase is separated, washedwith water, dried on Na₂ SO₄ and the solvents are evaporated in vacuum.The residue oil is crystallized from Et₂ O to yield1,3-di-o-methoxyphenoxy-propan-2-one (22 g) m.p. 64°-66° C.

Cysteamine acetate, obtained from cysteamine(2-amine-ethanethiol)hydrochloride (3.6 g) and sodium acetate (4.52 g)is added to a solution of 1,3-di-o-methoxyphenoxy-propan-2-one (8 g) inethanol (60 ml). The mixture is stirred for 3 days at room temperature,the ethanol is evaporated off and the residue is partitioned betweenwater and CH₂ Cl₂. The organic phases are collected, washed with water,dried on MgSO₄. After evaporation of the solvents under vacuum, the oilis crystallized from Et₂ O to give 7.8 g of2,2-di(o-methoxyphenoxy)methyl-thiazolidine m.p. 86°-88° C. (R_(f) =0.5on SiO₂ CH₂ Cl₂ /EtOAc 4:1). An analytical sample from ethanol showsm.p. 91°-93° C.

EXAMPLE 2

Following the procedure described in Example 1 but using L-cysteinehydrochloride, 2,2-di(o-methoxyphenoxy)methyl-4-carboxy-thiazolidinem.p. 160°-162° C. is obtained.

EXAMPLE 3

Following the procedure described in Example 1, but using L-cysteineethyl ester hydrochloride,2,2-di(o-methoxyphenoxy)methyl-4-carbethoxythiazolidine (EtOH), isobtained, as an oil, [α]_(D) -53°; [α]₃₆₅ =-138°.

EXAMPLE 4

Under an inert gas athmosphere a 1M DIBAH (diisobutylaluminum hydride)solution in toluene (150 ml) is added dropwise to a stirred solution of3,4-dihydrobenzopyran-2-one (20 g) in dry toluene (200 ml) cooled at-70° C., in 20 minutes.

Stirring is continued for additional 20 minutes, then the excess reagentis destroyed by adding a 2M isopropanol solution in toluene (50 ml). Themixture is warmed at room temperature and treated with water (5 ml) andanhydrous Na₂ SO₄ (40 g) under continuous stirring. The inorganicmaterial is filtered off and the organic eluate is evaporated to drynessunder vacuum to give crude 3,4-dihydro-2-hydroxy-benzopyrane (19.4 g).

A solution of this compound in EtOH (70 ml) is treated with an aqueoussolution of cysteamine acetate prepared by mixing cysteaminehydrochloride (18 g) and potassium acetate (16.2 g) in water (30 ml).

The reaction mixture is stirred for 30 minutes at room temperature anddiluted with water (200 ml). The precipitate is filtered and afterdrying in vacuum is crystallized from isopropylether to give2-[2'-(o-hydroxyphenyl)ethyl]thiazolidine (16 g) m.p. 100°-102° C.

α-Chloroacetylchloride (13.4 g, 9.5 ml) is added, with exclusion ofhumidity, under stirring, in 30 minutes, to a solution of the abovethiazolidine (12 g) in 1,2-dichloroethane (120 ml) and triethylamine (18ml), cooled at -10° C. Stirring is continued for 1 hour at 0° C. and themixture is partitioned with water. The organic phase is separated,washed with water, dried on CaCl₂ and the solvents are evaporated todryness in vacuum. Crystallization from Et₂ O gives3-α-chloroacetyl-2-[2'-(o-α-chloroacetoxy-phenyl)ethyl]thiazolidine (12g), m.p. 88°-89° C. (hexane/AcOEt 7:3, R_(f) =0.5). A solution of thiscompound (6 g) in acetone (30 ml) is treated with potassium thioacetate(4.1 g) under stirring for 30 minutes. The mixture is filtered from theinorganic materials, the acetone is evaporated under vacuum and theresidue is partitioned between water and EtOAc. From the organic phaseafter the usual work-up it is obtained3-acetylthioacetyl-2-[2'-(o-acetylthioacetoxyphenyl)ethyl]thiazolidineas a colourless oil (hexane/AcOEt 7:3, R_(f) =0.4).

EXAMPLE 5

A solution of3-chloroacetyl-2-[2'-(o-chloroacetoxyphenyl)ethyl]thiazolidine (5.5 g)in dry methanol is treated with p-toluenesulphonic acid (0.5 g) at roomtemperature for 2 days. The excess of solvent is evaporated in vacuumand then the mixture is diluted with water (80 ml). The crystallineprecipitate is collected by filtration, dried in vacuum andrecrystallized from Et₂ O to give 3.9 g of3-chloroacetyl-2-[2'-(o-hydroxyphenyl)ethyl]thiazolidine m.p. 98° C.

The same compound is obtained by treatment at -35° of a solution of2-[2'-(o-hydroxyphenyl)ethyl]thiazolidine (5 g) in 1,2-dichloroethane(50 ml) with triethylamine (3.8 ml) and chloroacetylchloride (2 ml),which is added dropwise in 15 minutes.

The organic phase is warmed at room temperature, washed with water,dried on CaCl₂ and the solvents are evaporated in vacuum to dryness. Theresidue gives 4.5 g of3-α-chloroacetyl-2-[2'-(o-hydroxyphenyl)ethyl]thiazolidine m.p. 96°-98°(from Et₂ O).

The obtained compound (3.5 g) is reacted in acetone (20 ml) withpotassium thioacetate (1.5 g) at room temperature for 1 hour to give3-acetylthioacetyl-2-[2'-(o-hydroxyphenyl)ethyl]thiazolidine (3.2 g), asa colourless oil (R_(f) 0.25 hexane/EtOAc 6:4).

H--NMR=2.35 (s, 3H, --S--CO--CH₃); 3.7 (s, 2H, --CO--CH₂ --S--CO;2.1-2.4 (2s, 4H, CH₂ --CH₂ 9; ##STR22##

EXAMPLE 6

Chloroacetyl chloride (8.4 ml) is added dropwise to a stirred mixture ofpyrocatechol (11 g), triethylamine (28 ml) and dry methylene chloride(100 ml), cooled at 0° C., in 20 minutes.

The mixture is warmed at room temperature, then heated to reflux for 2hours. The organic phase is washed with water, 5% aqueous sodiumhydroxyde and then with water. After drying on Na₂ SO₄, the solvent isevaporated to dryness under vacuum and the crude material is crytallizedfrom cyclohexane--Et₂ O to give 1,4-benzodioxan-2-one (10 g) m.p.52°-54° C. A molar solution of DIBAH in toluene (73 ml) is addeddropwise to a stirred solution of 1,4-benzodioxan-2-one (8.9 g) in drytoluene (100 ml), cooled at -70° C. during 40 minutes. Stirring at thistemperature is continued for 15 minutes, then the excess reagent isdestroyed by adding 2N-isopropanol in toluene (75 ml), under stirring,at -70°+-60° C. The mixture is warmed at room temperature and treatedwith 30% NaH₂ PO₄ aqueous solution (6 ml) and 25 g of anhydrous Na₂ SO₄,for 4 hours, under stirring. The inorganic material is filtered out andthe eluate is evaporated to dryness to give 8.2 g of2-hydroxy-1,4-benzodioxan. A stirred solution of this δ-lactol (7.8 g)in ethanol (30 ml) is treated with a solution of cysteaminehydrochloride (7.36 g) and potassium acetate (6.5 g) in water (12 ml).Stirring is continued for 45 minutes, then a crystalline precipitate of2-[(o-hydroxyphenoxy)methyl]thiazolidine(8.1 g) is obtained. M.p.76°-78° C.

EXAMPLE 7

Chloroacetylchloride (2.5 ml) is added to a stirred solution of2-[(o-hydroxyphenoxy)methyl]thiazolidine (6 g) in 1,2-dichloroethane (80ml) and triethilamine (4.3 ml) cooled at -30° C. After the usual work-up3-αchloroacetyl-2-[(o-hydroxyphenoxy)methyl]thiazolidine (5.7 g, fromEt₂ O, m.p. 89°-91° C.) is obtained. A stirred solution of the lattercompound in 1,2-dichloroethane (50 ml) is heated with solid potassiumthioacetate (4 g). After 2 hours, the mixture is washed with water togive, after the usual work-up,3-acetylthio-acetyl-2-[(o-hydroxyphenoxy)methyl]thiazolidine (6.4 g,from EtOH) m.p. 97°-99° C.

A stirred solution of this compound (2.5 g) in dimethoxyethane (25 ml)is treated with 30% aqueous ammonia (5 ml) in inert gas atmosphere.Stirring is continued for 5 hours, the reagents are evaporated to smallvolume in vacuum and the residual mixture is diluted with 30% NaH₂ PO₄aqueous solution (25 ml). After extraction of the aqueous medium withEt₂ O, the usual work-up gives3-mercaptoacetyl-2-[(o-hydroxyphenoxy)methyl]thiazolidine (1.22 g) m.p.92°-93° C.

EXAMPLE 8

A solution of3-α-chloroacetyl-2-[2'-(o-hydroxyphenoxy)methyl]thiazolidine (1 g) inDMSO (5 ml) is treated at room temperature with sodium-imidazolyl (0.58g). After 3 hours the mixture is poured in ice (20 g) and 30% NaH₂ PO₄aqueous solution (50 ml) and extracted with EtOAc. After the usualwork-up,3-(imidazol-1'-yl)acetyl-2-[(o-hydroxyphenoxy)methyl]thiazolidine (0.68g) is obtained as a colourless oil.

A solution of this compound in Et₂ O is treated with gaseous HCl and thecrystalline hydrochloride (m.p. 170° C.) is obtained.

EXAMPLE 9

Following the procedure described in Example 7, but using an excess ofα-chloro-acetylchloride, the following 2-substituted thiazoline areprepared:3-α-chloroacetyl-2-[(o-α-chloroacetoxyphenoxy)methyl]thiazolidine; m.p.88°-89° C.;3-α-acetylthioacetyl-2-](o-α-acetylthioacetoxyphenoxy)methyl]thiazolidine,as a colourless oil;

H--NMR=2.35 (2s, 6H, --S--CO--CH₃); 3.7-4 (2s, 4H, CH₂ --S--); 5.5 (t,1H, ##STR23## 7 (s, 4H, H on benzene ring).

EXAMPLE 10

α-Ortho-tolyloxy-ethanal (7.8 g) is reacted in ethanol (30 ml) with anaqueous solution of cysteamine acetate (6.4 10⁻² M). The mixture isstirred for 30 minutes at room temperature and poured in water (50 ml).

The precipitate is filtered and crystallized from petroleumether/isopropyl ether (3:1) to give 2-(o-tolyloxymethyl)thiazolidine (7g) m.p. 66°-68° C.

A solution of this compound (6.5 g) in dry 1,2-dichloroethane is cooledat 0° C. and treated with triethylamine (5 ml) and withα-chloroacetylchloride, added during 15 minutes. The mixture is stirredfor additional 20 minutes, then solid potassium thioacetate is added.After 1 hour, the inorganic material is removed by filtration and theorganic filtrate is washed with water.

After the usual work-up, the residual oil (13 g) is purified by columnchromatography on SiO₂, using a mixture of petroleum ether-Et₂ O 7:3 asthe eluent.

The recovered 3-acetylthioacetyl-2-(o-tolyloxymethyl)thiazolidine (9.51g) is a colourless oil, which can't be crystallized. H-NMR=2.2 (s, 3H,##STR24## 2.35 (s, 3H, S--CO--CH₃); 3.8 (d, 2H, O--CH₂ --CH); ##STR25##

EXAMPLE 11

Using potassium thiobenzoate in the procedure of the Example 10, the3-benzoylthioacetyl-2-[o-tolyloxymethyl]thiazolidine is obtained as anuncrystallizable colourless oil.3-Mercaptoacetyl-[2-o-tolyloxymethyl]thiazolidine m.p. 54°-56° C. isprepared by hydrolysis with aqueous ammonia, according to the procedureof the Example 7.

EXAMPLE 12

A solution of α-(o-methoxy)phenoxy ethanal (9 g) in ethanol (90 ml) isheated with a L-cysteine (6.71 g) solution in water (36 ml) and withacetic acid (5.4 ml), for a night at 50° C. After cooling at roomtemperature, the white precipitate is filtered out and crystallized fromEtOAc to give 4-carboxy-2-(o-methoxyphenoxymethyl)thiazolidine (9.3 g)m.p. 149°-150° C. [α]_(D) =-86°; [α]₃₆₅° =-226° (EtOH).

A solution of this compound (0.6 g) in dry acetone (10 ml) is heatedwith triethylamine (0.98 ml) and α-chloroacetylchloride (0.48 ml) for 2hours at room temperature. Potassium-thioacetate (1.14 g) is then addedto the mixture which is stirred for additional 3 hours at roomtemperature. The acetone is partially removed under vacuum and themixture is diluted with water and acidified to pH 6.5. After extractionwith ethylacetate and the usual work-up, 0.25 g of4-carboxy-2-(o-methoxyphenoxymethyl)-3-acetylthioacetylthiazolidine isobtained as a colourless oil, [α]_(D) =-24° (EtOH).

EXAMPLE 13

Following the procedure described in Example 12, but using an aqueoussolution of L-cysteine methyl ester hydrochloride and sodium acetate,4-carbomethoxy-2-(o-methoxy)phenoxymethyl-thiazolidine [α]_(D) =-57°(EtOH) and4-carbomethoxy-2-(o-methoxyphenoxymethyl)-3-acetylthioacetyl-thiazolidine[α]_(D) =-48° (EtOH) are prepared.

EXAMPLE 14

A mixture of [α-(o-methoxy)phenoxy]ethanal (7.9 g), L-cysteine ethylester (8.8 g), sodium acetate.3H₂ O (7.1 g) and ethanol (200 ml) isstirred at room temperature for 12 hours. The excess solvent isevaporated and the mixture is diluted with water, extracted with EtOAc.The combined organic phases are washed with water, aqueous NaHCO₃, thenwater, dried and evaporated to dryness, to give an oil (13 g). Furthercrystallization from hexane gives4-carbethoxy-2-(o-methoxyphenoxy)methyl-thiazolidine (12 g) m.p. 50° C.;[α]_(D) =-49° (EtOH). Subsequent treatment in acetone of this compound(8.5 g) with triethylamine (6.1 ml) and α-chloroacetylchloride (3.3 ml)and, without separation of the intermediate1-α-chloroacetyl-thiazolidine, with potassium-thioacetate (6.5 g) gives,after the usual work-up,4-carbethoxy-2-(o-methoxyphenoxy)methyl-3-acetylthioacetylthiazolidine(7 g) m.p. 90° (from Et₂ O) [α]_(D) =-41° (EtOH).

EXAMPLE 15

The reaction of 4-carbethoxy-2-(o-methoxy)phenoxymethyl-thiazolidine(7.5 g) in dry methylene chloride with ethoxalylchloride (3.1 ml) in thepresence of triethylamine (3.9 ml) for 2 hours at room temperature,gives 4-carbethoxy-2-(o-methoxyphenoxy)methyl-3-ethoxalyl-thiazolidine(8.5 g) as a colourless oil, [α]_(D) =-46° (EtOH) after the usualwork-up.

EXAMPLE 16

Following the procedure described in Example 15, but using theethoxysuccinoylchloride and the ethoxyglutaroylchloride, the followingcompounds are obtained:

4-carbethoxy-2-(o-methoxy-phenoxy)methyl-3-(3'-carbethoxy)propanoyl-thiazolidine[α]_(D) =-38° (EtOH);

4-carbethoxy-2-(o-methoxy-phenoxy)methyl-3-(4'-carbethoxy)butanoyl-thiazolidine[α]_(D) =-32° (EtOH).

EXAMPLE 17

Following the procedure described in Example 14, but usingα-[(o-ethoxy)phenoxy]ethanal, α-[(o-propargyloxy)phenoxy]ethanal,α-[(o-allyloxy)phenoxy]ethanal and α-[(o-methoxy)phenylthio]ethanal thefollowing compounds are obtained:

4-carbethoxy-2-(o-ethoxy-phenoxy)methyl-thiazolidine, [α]_(D) =-56°(EtOH);

4-carbethoxy-2-(o-ethoxy-phenoxy)methyl-3-α-acetylthioacetyl-thiazolidine,[α]_(D) =-39° (EtOH);

4-carbethoxy-2-(o-propargyloxy-phenoxy)methyl-thiazolidine, [α]_(D)=-81° (EtOH);

4-carbethoxy-2-(o-propargyloxy-phenoxy)methyl-3-α-acetylthioacetyl-thiazolidine,[α]_(D) =-71° (EtOH);

4-carbethoxy-2-(o-allyloxy-phenoxy)methyl-thiazolidine, [α]_(D) =-62°(MeOH);

4-carbethoxy-2-(o-allyloxy-phenoxy)methyl-3α-acetylthioacetyl-thiazolidine[α]_(D) =-66° (MeOH);

4-carbethoxy-2-(o-methoxy-phenylthio)methyl-thiazolidine [α]_(D) =-59°(MeOH);

4-carbethoxy-2-(o-methoxy-phenylthio)methyl-3α-acetylthioacetyl-thiazolidine[α]_(D) =-49° (MeOH);

4-carboxy-2-(o-methoxyphenylthio)methyl-thiazolidine [α]_(D) =-75.5°;[α]₃₆₅ =-168° (MeOH).

EXAMPLE 18

o-Methoxy-thiophenol (83.5 g) is reacted in DMF (150 ml) withα-bromoethanal dimethyl acetale (76.2 ml) in the presence of dry K₂ CO₃(81.4 g), under stirring, in inert gas atmosphere for 2 hours at 50° C.The mixture is cooled and after filtration of the inorganic material itis diluted with water (500 ml) and extracted with Et₂ O. The collectedorganic phases are dried on Na₂ SO₄ and evaporated to dryness to give 85g of α-(o-methoxyphenylthio)ethanal dimethyl acetal as a colourless oil.

A solution of this compound in methanol (400 ml) is treated with 2N H₂SO₄ (100 ml) for 2 hours at 80°, the excess methanol is evaporated invacuum and the residue is diluted with water and extracted with Et₂ O.The usual work-up gives α-(o-methoxyphenylthio)ethanal (70.2 g).

15.5 g of this latter substance is reacted in water (50 ml) withcysteamine hydrochloride (8 g) and potassium acetate (6.56 g), understirring for 2 hours at room temperature. Addition of methylenechloride(30 ml) and the usual work-up of the organic phase give a crude oil (13g) which is crystallized from isopropanol to yield2-(o-methoxyphenylthio)methyl-thiazolidine m.p. 111°-112° C.

Using in this procedure α-(o-methoxy-phenoxy)ethanal,α-(o-ethoxyphenoxy)ethanal, α-(o-allyloxyphenoxy)ethanal andα-(o-propargyloxyphenoxy)ethanal the following 2-substitutedthiazolidines are obtained:

2-(o-ethoxyphenoxymethyl)thiazolidine m.p. 60°-64° C.;

2-(o-methoxyphenoxymethyl)thiazolidine m.p. 62°-63° C.;

2-(o-allyloxyphenoxymethyl)thiazolidine m.p. 55°-56° C.;

2-(o-propargyloxyphenoxymethyl)thiazolidine m.p. 72°-74° C.

EXAMPLE 19

A solution of 2-(o-methoxphenoxymethyl)thiazolidine (100 g) in1,2-dichloroethane (250 ml) cooled at 10° is heated, under stirring,with triethylamine (68 ml) and a solution of α-chloroacetylchloride(36.2 ml) in 1,2-dichloroethane (50 ml) is added dropwise. After 1 hour,the mixture is washed with water, dried on Na₂ SO₄ and evaporated todryness. Subsequent crystallization from propan-2-ol gives3-α-chloroacetyl-2-(o-methoxyphenoxymethyl)thiazolidine m.p. 87°-88° C.(100 g).

EXAMPLE 20

A solution of 2-(o-methoxyphenoxymethyl)thiazolidine (15 g) in acetone(75 ml), cooled at 10° C., under stirring is added with triethylamine(10.5 ml) and dropwise with a solution of α-chloroacetylchloride (5.8ml) in acetone (15 ml). After 2 hours the mixture is added withpotassium thioacetate (35.4 g) and stirring is continued for 2 hours,the mixture is poured in ice and water (250 ml) and the precipitate isfiltered and crystallized from EtOH to give2-(o-methoxyphenoxy)methyl-3-acetylthioacetylthiazolidine (19.8 g, 87%yield) m.p. 89°-91° C.

EXAMPLE 21

A solution of 3-α-chloroacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine(6 g) in acetone (80 ml) is heated to reflux temperature in the presenceof sodium iodide (5 g) for 3 hours and then poured in ice and water (400ml). The precipitate is collected, dissolved in methylene dichloride andwashed with water, 5% aqueous NaHCO₃, 2N sodium thiosulphate, water anddried on Na₂ SO₄. After the usual work-up, the residue is crystallizedfrom acetone and isopropanol to give 5.92 g of3-α-iodoacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine m.p. 81°-83° C.Using this procedure sodium bromide, the3-α-bromoacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine is obtained,m.p. 82°-84° C.

EXAMPLE 22

A solution of a 3-α-haloacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine(for example the 1-α-bromoacetyl, 2.07 g) in 1,2-dichloroethane (20 ml)is treated under stirring with 3,4,5-trimethoxy-thiobenzoic acid (m.p.172°-174° C. obtained from 3,4,5-trimethoxybenzoylchloride and NaSH inaqueous ethanol) in the presence of aqueous solution of potassiumcarbonate (2 g) and tetrabutylammonium bromide (0.32 g). After a night,the organic phase is separated, washed with water, dried on CaCl₂.Afther the usual work-up and filtration on short column of SiO₂ withhexane/AcOEt 3:1,3-(3',4',5'-trimethoxy-benzoyl)thioacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine(2.2 g) is obtained, m.p. 110°-112° C.

Using in this procedure the thiobenzoic acid and the thionicotinic acid,the following compounds are obtained:

3-benzoylthioacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine, m.p.84°-86° C.;

3-nicotinoylthioacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine m.p.89°-91° C., hydrochloride m.p. 138°-139°, methansulphonate m.p.122°-124° C.

EXAMPLE 23

Under an inert gas athmosphere, 30% ammonium hydroxyde (10 ml) is addedto a stirred solution of3-acetylthioacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine (3.5 g) in1,2-dimethoxyethane (20 ml). After 2 hours the mixture is diluted withwater (120 ml) and the precipitate is filtered, dried under vacuum,crystallized from ethyl ether to give3-mercaptoacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine (2.4 g) m.p.86°-87° C.

A solution of this compound (0.8 g) in dry pyridine (3.2 ml) is treatedwith cyclopentylpropionyl-chloride (0.5 g). After a night, the mixtureis diluted with 2N H₂ SO₄, extracted with Et₂ O to afford after theusual work-up3-(3'-cyclopentyl)propionylthioacetyl-2(o-methoxyphenoxy)methyl-thiazolidine(0.92 g) m.p. 48°-49° C.

In the same way, using 3-cyclohexylpropionylchloride,3-phenylpropionylchloride and cyclopropylcarbonylchloride instead of3-cyclopentylpropionylchloride the following compounds are obtained:

3-(3'-cyclohexyl)propionylthioacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine,m.p. 44°-45° C.;

3-(3'-phenyl)propionylthioacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine,m.p. 38°-44° C.;

3-(cyclopropylcarbonylthioacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine,m.p. 99°-101° C.

EXAMPLE 24

Following the procedure of Example 23, but using phenoxyacetylchloride,ethoxyoxalylchloride, ethoxycarbonylchloride, the followingthiazolidines are obtained:

3-phenoxyacetylthioacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine m.p.64°-66° C.;

3-ethoxyalylthioacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine m.p.64°-66° C.;

3-ethoxycarbonylthioacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine m.p.72°-76° C.

EXAMPLE 25

A solution of 2-(o-methoxyphenoxy)ethanal (0.45 g) in ethanol (10 ml)and few drops of acetic acid are added to a solution of L-penicillamine(3-mercapto-D-valine, 0.45 g) in ethanol (20 ml), the mixture is stirredat room temperature for 3 hrs. The solvent is evaporated in vacuum to asmall volume, the residue is diluted with water and extracted withethylacetate. After the usual work-up, the residual oil is crystallizedfrom ethanol to give2-(o-methoxyphenoxy)methyl-4,4-dimethyl-5-carboxy-thiazolidine m.p.136°-138° C.

In similar way, starting from 3-mercapto-D-valine ethylester, thefollowing compounds are obtained:

2-(o-methoxyphenoxy)methyl-4,4-dimethyl-5-carbethoxy-thiazolidine[α]_(D) =+13° (MeOH); and

3-acetylthioacetyl-2-(o-methoxphenoxy)methyl-4,4-dimethyl-5-carbethoxy-thiazolidine[α]_(D) =+24° (MeOH).

EXAMPLE 26

A monoperphtalic acid solution (41 ml, 66.5 mg/ml) in ethyl acetate isadded to a stirred solution of3-chloroacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine (7 g) in ethylacetate cooled at 0° C. After 2 hours the mixture is washed with 5%aqueous NaHCO₃, aqueous sodium sulphite, 5% aqueous NaHCO₃ and water.The organic phase is dried on Na₂ SO₄ and the solvent is evaporated todryness in vacuum. The residue is crystallized from ethanol to give3-chloroacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine-1-sulphoxide.(5.62 g) m.p. 127°-128° C.

A solution of this sulphoxide (4.68 g) in 1,2-dichloroethane (40 ml) isreacted with dry potassium-thioacetate (2 g) for 2 hours at roomtemperature under stirring. After the usual work-up3-acetylthioacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine-1-sulphoxideis obtained, m.p. 112°-114° C.

EXAMPLE 27

Following the procedure described in Example 22, but using3-chloroacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine-1-sulphoxide, thefollowing thiazolidines are prepared:

3-benzoylthioacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine-1-sulphoxidem.p. 110°-112° C.;

3-(3,4,5-trimethoxybenzoyl)thioacetyl-(2-o-methoxyphenoxy)methyl-thiazolidine-1-sulphoxidem.p. 122°-124° C.

EXAMPLE 28

Imidazolyl sodium (3.58 g) is added to a stirred solution of3-chloroacetyl-2-(o-methoxyphenoxy)methylthiazolidine (5.8 g) in DMSO(35 ml). After 1 hour the mixture is poured in ice and water (200 ml)and the separated oil is extracted with EtOAc (3×30). The organic phasesare collected, washed with water, dried on Na₂ SO₄. After evaporation,the crude residue is purified by filtration on a short column of SiO₂using EtOAc and EtOAc/MeOH 85:15 as the eluent to give3-(imidazol-1-yl)acetyl-2-(o-methoxyphenoxy)methyl-thiazolidine (5.1 g)as a colourless oil.

A stirred solution of this compound in isopropanol (25 ml) and Et₂ O (35ml) is treated with 7,7N aqueous nitric acid (2.1 ml). After 2 hours thecrystalline precipitate is collected by filtration, washed with Et₂ O(30 ml) and dried under vacuum to give3-(imidazol-1-yl)acetyl-2-(o-methoxyphenoxy)methyl-thiazolidine nitrate,m.p. 139°-140° C.

EXAMPLE 29

Potassium carbonate (3.8 g) and N-methylpiperazine (3.2 g) are added toa stirred solution of3-chloroacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine (8 g) inacetonitrile (48 ml). The mixture is heated to reflux temperature for 1hour, the excess solvent is removed in vacuum and the residue ispartitioned between water and EtOAc. The usual work-up gives 5.5 g of3-(4'-methyl-piperazin-1'-yl)acetyl-2-(o-methoxyphenoxy)methyl-thiazolidineas a colourless oil.

Its hydrochloride (m.p. 212°-214°) is formed and crystallized from2-propanol.

EXAMPLE 30

Following the same procedure described in Example 29, using thefollowing amines: morpholine, piperidine, N-m-chlorophenylpiperazine,N-phenylpiperazine; the following thiazolidines are obtained:

3-morfolylacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine hydrochloridem.p. 88°-88.5° C.;

3-piperidyl-2-(o-methoxyphenoxy)methyl-thiazolidine as a colourless oil,hydrochloride 90°-92° C.;

3-(4'-m-chlorophenyl-piperazin-1'-yl)-2-(o-methoxyphenoxy)methyl-thiazolidineas a colourless oil, bis methanesulphonate m.p. 60° C., bis.HCl m.p.178°-180° C.;

3-(4'-phenylpiperazin-1'-yl)-2-(o-methoxyphenoxy)methyl-thiazolidinem.p. 52°-54° C.; hydrochloride 134°-136° C.

ESAMPLE 31

To a cooled solution of N-methylpiperazino acetic acid (1.73 g) andtriethylamine (1.52 ml) in dichloromethane is added a solution ofisobutylchloroformate (1.44 ml) in dichloromethane (6 ml). The mixtureis stirred for 45 minutes at -10° C., then3-mercaptoacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine (3.4 g)dissolved in dichloromethane (10 ml) is added. The mixture is kept for45 minutes at -10° C. then it is warmed at room temperature.

After the usual work-up,3-(4'-methylpiperazin-1-yl)acetylthioacetyl-2-(o-methoxyphenoxy)methyl-thiazolidineis obtained as vitreous oil.

A solution of this compound (4.78 g) in acetone (25 ml) is treated withgaseous HCl: its bis.hydrochloride, precipitates with m.p. 178°-180° C.Using in this procedure morfolinoacetic,4-m-chlorophenyl-piperazinoacetic,N,N-diethylaminoacetic acids, thecorresponding thiazolidines are obtained:

3-(1-morfolyl)acetylthioacetyl-2-(o-methoxyphenoxy)methyl-thiazolidinem.p. 165°-168° C. (as HCl salt);

3-diethylaminoacetylthioacetyl-2-(o-methoxyphenoxy)methyl-thiazolidinem.p. 142°-150° C. (as HCl salt);

3-(4'-m-chlorophenyl)acetylthioacetyl-2-(o-methoxyphenoxy)methyl-thiazolidinem.p. 182°-186° C. (as HCl salt).

EXAMPLE 32

α-Bromopropionyl chloride (0.97 ml) in methylene chloride (15 ml) isadded dropwise to a mixture of 2-(o-methoxyphenoxy)methyl-thiazolidine(2 g) and triethylamine (1.35 ml) in CH₂ Cl₂ (30 ml) at 0°-5° C. After 1hour, the mixture is washed with water and the usual work-up gives3-α-bromopropionyl-2-(o-methoxyphenoxy)methyl-thiazolidine as acolourless oil.

The compound is reacted with an excess of potassium-thioacetate (1.8 g)in acetone (15 ml) to give after the usual work-up,3-(acetylthio)propionyl-2-(o-methoxyphenoxy)methyl-thiazolidine (1.8 g)as an uncrystallizable oil. After 2 months, this sample, maintained at-20° C., shows some crystalline seeds. Further crystallization from Et₂O fives 0.83 g of a diasteroisomeric couple m.p. 101°-102° (SS,RR) andan uncrystallizable oil (SR, RS). Even though the absoluteconfigurations of the chiral center have been defined on the basis ofH-NMR spectra, they cannot be considered definitively ascertained.

EXAMPLE 33

A solution of 2-(o-methoxyphenylthio)methyl-thiazolidine (5 g) inpyridine (25 ml) is reacted with acetylthioacetylchloride (2.93 g) for anight at room temperature, the reaction mixture is diluted with 2N H₂SO₄, extracted with ethylether to give after the usual work-up3α-acetylthioacetyl-2-(o-methoxyphenylthio)methyl-thiazolidine, m.p.62°-64° C.

In a similar way the following compounds are obtained:

2-(o-ethoxyphenoxy)methyl-3-acetylthioacetyl-thiazolidine;

2-(o-allyloxyphenoxy)methyl-3-acetylthioacetyl-thiazolidine;

2-(o-propargyloxyphenoxy)methyl-3-acetylthioacetyl-thiazolidine;

4-carboxy-2-(o-methoxyphenylthio)methyl-3-acetylthioacetyl-thiazolidine[α]_(D) =-39° (MeOH).

EXAMPLE 34

A solution of 2-(o-methoxyphenoxy)methyl-thiazolidine (1.83 g) inpyridine (6 ml) is treated with methane sulphonyl chloride (1.2 g) atroom temperature. After 4 hours the mixture is diluted with 2N H₂ SO₄,extracted with Et₂ O, to afford after the usual work-up 2.2 g of3-methanesulphonyl-2-(o-methoxyphenoxy)methyl-thiazolidine m.p.118°-120° C.

EXAMPLE 35

Following the procedure described in Example 34, but using the followingacylating agents: p-toluensulphonylchloride, benzensulphonylchloride,acetic anhydride, trifluoroacetic anhydride, succinic anhydride,glutaric anhydride, cyclopropylcarbonylchloride, ethoxyoxalylchloride,the following thiazolidines are obtained:

3-p-tolylsulphonyl-2-(o-methoxyphenoxy)methyl-thiazolidine m.p.131°-133° C.;

3-phenylsulphonyl-2-(o-methoxyphenoxy)methyl-thiazolidine m.p. 124°-126°C.;

3-acetyl-2-(o-methoxyphenoxy)methyl-thiazolidine m.p. 84°-85° C.;

3-trifluoroacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine m.p. 78°-81°C.;

3-(3'-carboxy-propionyl)-2-(o-methoxyphenoxy)methyl-thiazolidine m.p.122°-124° C.;

3-(4'-carboxy-butirroyl)-2-(o-methoxyphenoxy)methyl-thiazolidine m.p.122°-124° C.;

3-ethoxyoxalyl-2-(o-methoxyphenoxy)methyl-thiazolidine m.p. 88°-91° C.;

3-cyclopropylcarbonyl-2-(o-methoxyphenoxy)methyl-thiazolidine m.p.82°-83° C.

EXAMPLE 36

Reaction in pyridine (5 ml) of 2-(o-methoxyphenoxy)methyl-thiazolidine(0.9 g) with α-bromo-isobutirroylchloride (0.54 ml) for 30 minutes at 0°C. followed by 2 hours at room temperature gives2-(o-methoxyphenoxy)methyl-3α-(2'-bromo-2'-methylpropionyl)thiazolidineas an oil.

H-NMR=1.6 (6H, 2S, ##STR26## 3.5 (3H, S, OCH₃).

EXAMPLE 37

A solution of α-(o-methoxyphenylthio)ethanal dimethylacetal (6.2 g),cysteamine hydrochloride (4.6 g) and potassium acetate (3.92 g) in 70%aqueous acetic acid is heated for 2 hours at 100° C. The mixture ispoured in an excess of 7% aqueous sodium hydrogenocarbonate and ice andthe precipitate is collected by filtration affording, aftercrystallization from acetone-isopropylether, 5 g of2-(o-methoxyphenylthio)methyl-thiazolidine m.p. 111°-112° C.

Subsequent treatment with α-chloroacetylchloride gives3α-chloroacetyl-2-(o-methoxyphenylthio)methyl-thiazolidine m.p.127°-129° C. which is converted by treatment with potassium thioacetateinto 3-acetylthioacetyl-2-(o-methoxyphenylthio)methyl-thiazolidine oil;H-NMR (CDCl₃): 7 (m, 4H, Arom); 3.95 (s, 3H, OCH₃); 3.8 (d, 2H, S--CH₂--); 2.4 (s, 3H, ##STR27##

Starting from the same α-chloroacetyl compound (1.65 g) by reaction inacetonitrile with 4-methylpiperazine (1.5 ml) in the presence ofpotassium carbonate (1.5 g) for a night at room temperature, after theusual work-up3-(4'-methylpiperazin-1'-yl)acetyl-2-(o-methoxyphenylthio)methyl-thiazolidineis obtained m.p. 144°-146° C.; bis-hydrochloride salt m.p. 203°-205° C.

Starting from the3-(acetylthioacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine byammonolysis, according to the procedure of Example 23, and subsequentesterification with 4-methyl-piperazin-1-ylacetic acid mixed anhydride3-(4'-methylpiperazin-1'-yl)acetylthioacetyl-2-(o-methoxyphenylthio)methyl-thiazolidine,free base is obtained as an oil; bis-hydrochloride m.p. 165°-169° C.

EXAMPLE 38

A solution of 3α-iodoacetyl-2-(o-methoxphenoxy)methyl-thiazolidine (3.9g) in benzene (25 ml) is treated with triphenylphosphine (2.7 g) at thereflux temperature for 2 hours. The solution is cooled at roomtemperature and the crystalline compound formed is separated byfiltration to give 4.2 g of 3-triphenylphosphoniumacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine iodide m.p. 165°-171° C.

Starting from the 3-chloro compound, the correspondingtriphenylphosphonium chloride (m.p. 174°-177° C.) is obtained.

This latter (5.5 g) is dissolved in water (30 ml) and methylene chloride(30 ml) is added. The mixture is vigorously stirred and 0.1N sodiumhydroxyde is added until a persistent light red color is developed inthe presence of phenolphthaleine. The organic phase is separated, washedwith water, dried and evaporated to dryness to yield 4.1 g (fromethylacetate) of3-triphenylphosphilyldenemethylcarbonyl-2-(o-methoxyphenoxy)methylthiazolidinem.p. 131°-135° C.

3 Grams of this ylide is treated in dimethoxyethane (12 ml) with4-acetoxy-3-methoxy-benzaldehyde (1.16 g) for 3 hrs at room temperature.The mixture is evaporated to dryness and filtered on short SiO₂ columnusing as the eluent hexane-AcOEt 15:10 to give pure3-E(4'-acetoxy-3'-methoxy)cinnamoyl-2-(o-methoxyphenoxy)methyl-thiazolidine-)as an oil; H-NMR: 2.3 (s, 3H, COCH₃); 3.7 (s, 3H), ##STR28##

A solution of 0.8 g of this latter compound in dry ethanol (5 ml) istreated at room temperature with finely powdered K₂ CO₃ (0.2 g), for anight, under stirring. The inorganic material is filtered out and themixture is poured in water, extracted with ethylacetate affording, afterthe usual work-up, 0.7 g of3-E(4'-hydroxy-3'-methoxy)cinnammoyl-2-(o-methoxyphenoxy)methyl-thiazolidine,oil, H-NMR: ##STR29##

Following the same procedure, but using 3,4-diacetoxy-benzaldehyde thefollowing compounds are prepared:

3-E(3',4'-diacetoxy)cinnamoyl-2-(o-methoxyphenoxy)methyl-thiazolidine;H-NMR: 2.28 (s, 6H, ##STR30## 3.88 (s, 3H, OCH₃); 7.88-7.05 (m, 2H,##STR31##3-E(3',4'-dihydroxy)cinnamoyl-2-(o-methoxyphenoxy)methyl-thiazolidine;H-NMR: 3.88 (s, 3H, --OCH₃); ##STR32##

EXAMPLE 39

To a solution of3α-chloroacetyl-2-[2'-(o-hydroxyphenyl)ethyl]-thiazolidine (2.5 g) inmethylene chloride (15 ml), 1,2-dihydropyrane (1 g) andp-toluensulphonic acid (50 mg) are added. The mixture is stirred for 2.5hours at room temperature then pyridine (0.1 g) is added and the solventis evaporated under vacuum. According to the procedure of Example 8, theresidue is dissolved in DMSO and heated with imidazolyl sodium. Afterthe usual work-up the intermediate3-(imidazol-1-yl)acetyl-2-[2'-(o-hydroxyphenyl)ethyl]-thiazolidine-2"-tetrahydropyranylether(2.4 g) obtained is treated with 2N methanolic hydrochloric acidsolution and the crystalline3-(imidazol-1-yl)acetyl-2-[2'-(o-hydroxyphenyl)ethyl]-thiazolidinehydrochloride, m.p. 178°-181° C. is precipitated by dilution of themixture with ethylether.

EXAMPLE 40

A solution of 2-(o-methoxyphenoxy)methyl-thiazolidine (0.98 g) inpyridine (4 ml) is reacted with succinic anhydride (0.4 g) for 2 hoursat room temperature. The mixture is diluted with 2N aqueous sulphuricacid until pH 4.5, then with water. The crystalline precipitate isfiltered and crystallized from aqueous ethanol to give2-(o-methoxyphenoxy)methyl-3-(3'-carboxy)propionyl-thiazolidine (0.95 g)m.p. 104°-107° C.

In similar way, using benzoylchloride, 3,4,5-trimethoxybenzoylchloride,nicotinoylchloride and 3-carboethoxy-propionylchloride the following3-acetylthiazolidines are obtained:

2-(o-methoxyphenoxy)methyl-3-(3'-carbethoxy)propionyl-thiazolidine, oil,H-NMR (CDCl₃): 6.90 (s, 4H, arom.); 3.8 (s, 3H, OCH₃); 4.15 (q, 2H, CH₂CH₃); 5.7 (t, 1H, ##STR33## 1.35 (t, 3H, CH₂ --CH₃);2-(o-methoxyphenoxy)methyl-3-benzoyl-thiazolidine m.p. 74°-76° C.;

2-(o-methoxyphenoxy)methyl-3-(3',4',5'-trimethoxy)benzoyl-thiazolidine,oil, H-NMR (CDCl₃) 6.8 (s, 4H, arom); 6.75 (s, 2H, arom.); 5.75 (t, 1H,##STR34## 3.75 (s, 12H, 4OCH₃);2-(o-methoxyphenoxy)methyl-3-nicotinoyl-thiazolidine m.p. 98°-100° C.

EXAMPLE 41

Tert-butylcarbonate (19.3 g) is added to a stirred solution of2-[2'-(O-hydroxyphenyl)ethyl]-thiazolidine (18.5 g) in dimethylformamide(20 ml) at room temperature. After 1 hour, the mixture is diluted withwater (200 ml) and the crystalline precipitate is filtered out to give2-[2'-(O-hydroxyphenyl)ethyl]-3-BOC-thiazolidine (26.5 g), m.p.113°-114° C.

In similar way the following BOC-thiazolidine are prepared:

2-[2'-(O-hydroxyphenyl)ethyl]-3-BOC-4-carboethoxy-thiazolidine, oil,H-NMR (CHCl₃ -THMS): 1.3 (3H, t, CH₂ --CH₃); 1.5 (9H, s, --C(CH₃)₃); 3.3(2H, d, s); 4.3 (2H, q, CH₂ --CH₃); 6.7-7.2 (4H, m);

2-(2'-O-hydroxyphenoxy)methyl-3-BOC-thiazolidine, m.p. 110° C.;

2-(2'-O-hydroxyphenoxy)methyl-3-BOC-4-carbethoxy-thiazolidine, oil H-NMR(CHCl₃ -THMS): 1.5 (9H, s, --C(CH₃)₃).

EXAMPLE 42

A solution of 2-(2'-O-hydroxyphenoxy)methyl-3-BOC-thiazolidine (1 g) inanhydrous DMF (10 ml) is stirred with 0.3 ml of allyl bromide andpotassium carbonate (1 g) for 5 hours. After dilution with water (100ml) and extraction with ethyl ether (2×30 ml), the organic phase arewashed with water, dried on Na₂ SO₄ and evaporated to dryness.

The residue 2-(2'-O-allyloxyphenoxy)methyl-3-BOC-thiazolidine (oil:H-NMR (CDCl₃ --THMS): 1.4 (9H, s, C(CH₃)₃ ; 4.55 (2H, d, --CH₂ --CH═);5.6-5 (3H, m, CH₂, ##STR35## 6.4-5.6 (1H, m, --CH═) is treated indichloromethane (5 ml) with trifluoroacetic acid (4 ml) and stirred for1 hour at room temperature. The mixture is evaporated to dryness invacuum, the residue is partitioned between 5% aqueous KHCO₃ anddichloromethane to give, after the usual work-up2-(2'-O-allyloxyphenoxy)methyl-thiazolidine, m.p. 49°-51° C. Ananalytical sample has m.p. 55°-56° C.

Using in the same procedure the propargyl chloride, the followingderivatives are prepared:

2-(2'-O-propargyloxyphenoxy)methyl-3-BOC-thiazolidine, m.p. 83°-85° C.;

2-(2'-O-propargyloxyphenoxy)methyl-thiazolidine, m.p. 78°-79° C. (fromethanol).

EXAMPLE 43

A solution of 3-morpholinomethyl-4-hydroxy-5-methoxy-benzaldehyde (5.02g) in ethylacetate (50 ml) is treated with3-triphenylphosphilydene-methylcarbonyl-2-(O-methoxyphenoxy)-methyl-thiazolidine(11.8 g) at room temperature. After 2 days, the mixture is extractedwith 12% aqueous HCl (5×50 ml). The combined aqueous extracts aretreated with 20% aqueous NaOH until pH 5 and then with 5% aqueous NaHCO₃until pH 7.8-8, extracted with dichloromethane (2×25 ml) to give a crudematerial which is purified by SiO₂ column chromatography(hexane:ethylacetate 1:1).

The oil (5.3 g) is treated in ethylacetate with 6N HCl in isopropanol togive3-(3'-morpholinomethyl-4'-hydroxy-3'-methoxy-cinnamoyl)-2-(O-methoxyphenoxy)methyl-thiazolidinehydrochloride (4.9 g) m.p. 124°-126° C.

In similar way the following compounds are prepared:

3-(3'-pyrrolidylmethyl-4'-hydroxy-5'-methoxy-cinnamoyl)-2-(O-methoxyphenoxy)methyl-thiazolidine-hydrochloride,m.p. 134°-136° C.;

3-(3'-morpholinomethyl-4'-hydroxy-5'-methoxy-cinnamoyl)-2-(O-hydroxyphenoxy)methyl-thiazolidinemaleate;

3-(3'-diethylaminomethyl-4'-hydroxy-5'-methoxycinnamoyl)-2-(O-propargyloxyphenoxy)methyl-thiazolidine-hydrochloride.

EXAMPLE 44

Using in the procedure of the Example 3 the following aldehydes:

2-(4-methyl-piperazin-1'-yl)ethanal

2-(morpholin-1'-yl)ethanal

3-(morpholin-1'-yl)propanal and propanal

the following 3-substituted thiazolidines are prepared:

3-[4-4-methylpiperazin-1-yl)-2-butenoyl]-2-(O-methoxyphenoxy)methyl-thiazolidinemaleate;

3-[4-(morpholin-1-yl)-2-butenoyl]-2-(O-methoxyphenoxy)methyl-thiazolidine-hydrochloride;

3-[5-(morpholin-1-yl)-2-pentenoyl]-2-(O-methoxyphenoxy)methyl-thiazolidine-hydrochloride;

3-(2-pentenoyl)-2-(O-methoxyphenoxy)methyl-thiazolidine.

EXAMPLE 45

A solution of acryloylchloride (12.2 ml) in CH₂ Cl₂ is added to astirred solution of 2-(O-methoxyphenoxy)methyl-thiazolidine (30.5 g) andtriethylamine (20.7 ml) in CH₂ Cl₂ (130 ml), cooled at 0°-5° C. Themixture is kept for 3 hours at 0°-5° C., the triethylamine hydrochlorideis removed by filtration and the eluate is washed with water, 5% aqueousNaHCO₃, water. After drying on Na₂ SO₄, and evaporation of the solvent,the crude residue is crystallized from ethylacetate to give3-acryloyl-2-(O-methoxyphenoxy)methyl-thiazolidine m.p. 56°-58° C. Usingin the procedure the 2-(O-hydroxyphenoxy)methyl-thiazolidine and coolingthe reaction mixture at -15°--10° C., the3-acryloyl-2-(O-hydroxyphenoxy)methyl-thiazolidine is obtained. Asolution of these acryloylthiazolidines (1.1 g) in ethanol (20 ml) aretreated with (2-hydroxyethylamino)ethylamine (0.42 ml).

The reaction mixture is kept for 28 hours at room temperature andevaporated to dryness. The residue is partitioned between water andethylacetate. The organic phase is separated, washed with water, driedon Na₂ SO₄ and evaporated to dryness.

A solution of the residual oil (1.6 g) in dry acetone (20 ml) is treatedwith a solution of maleic acid (0.48 g) in acetone (6 ml) to give acrystalline precipitate, yielding:

3-(3-(2-hydroxyethylamino)ethyl)aminopropanoyl-2-((O-methoxyphenoxy)methyl-thiazolidinebis maleate m.p. 128°-130° C.;

3-(3-(2-hydroxyethylamino)ethyl)aminopropanoyl-2-(O-hydroxymethyl)thiazolidinebis maleate m.p. 134°-136° C.;

3-(3-(2-hydroxyethylamino)ethyl)aminopropanoyl-2-(O-propargyloxy-methyl)thiazolidinebis maleate.

EXAMPLE 46

In inert gas atmosphere, cysteamine hydrochloride (0.38 g) is treatedwith 2-(O-methoxyphenoxymethyl)-3-acryloyl-thiazolidine (0.8 g) inethanol (25 ml) for 12 hours at room temperature and then for 8 hours atreflux temperature.

The reaction mixture is cooled at room temperature and after two daysthe crystalline precipitate is filtered to give 0.62 g of3-(5-amino-4-thia-hexanoyl)-2-(O-methoxyphenoxy)methyl-thiazolidine-hydrochloridem.p. 116°-118° C.

Using in the same procedure N-acetyl-cysteine, in the presence ofcatalytic amount of sodium methylate,

3-(5-carboxy-5-acetylamino-4-thia-hexanoyl)-2-(O-methoxyphenoxy)methyl-thiazolidinem.p. 119°-121° C., is prepared.

EXAMPLE 47

By treatment of the above described acryloythiazolidine in ethanol withimidazole, the following compounds are prepared:

3-(3-imidazol-1-yl)-propionyl-2-(O-propargyloxyphenoxy)methyl-thiazolidine;

3-(3-imidazol-1-yl)-propionyl-2-(O-methoxyphenoxy)methyl-thiazolidinem.p. 115°-117° C. (as nitrate).

EXAMPLE 48

A solution of 2-morpholine-ethylchloride hydrochloride (0.18 g) in water(5 ml) is added to a solution of3-(2-mercaptoacetyl)-2-(O-methoxyphenoxy)methyl-thiazolidine in aqueousN sodium hydroxyde (10 ml), in inert gas atmosphere and stirredovernight at room temperature.

The aqueous phase is extracted with ethylether, and the combined organicphase are collected, washed with NaOH, water, dried on Na₂ SO₄ andevaporated to dryness to give3-[5-(morpholin-1-yl)-3-thia-pentanoyl)-2-(O-methoxyphenoxy)methyl-thiazolidine(oil), hydrochloride m.p. 158°-160° C.

EXAMPLE 49

A solution of 1-iodo-pentane (0.21 ml) in methanol (2 ml) is added to asolution of 3-(2-mercaptoacetyl)-2-(O-methoxyphenoxy)methyl-thiazolidine(0.5 g) in a sodium methylate solution (from 42 mg of sodium in 10 ml ofmethanol). The mixture is stirred for 3 hours at room temperature,diluted with N aqueous sodium hydroxide (60 ml) and then extracted withethylacetate to give, after the usual work-up, 0.44 g of3-(3-thia-octanoyl)-2-(O-methoxyphenoxy)methyl-thiazolidine oil. Usingin this procedure the α-bromomethylacetate as alkylating agent, the3-(4-carbomethoxy-3-thia-succinoyl)-2-(O-methoxyphenoxy)methyl-thiazolidine,m.p. 77°-79° C., is obtained.

EXAMPLE 50

A solution of dicyclohexylcarbodiimide (1.75 g) in dimethylformamide (10ml) is added to a stirred suspension of phenylthioacetic acid (1.44 g)and 2-(O-hydroxyphenoxy)methyl-thiazolidine in dimethylformamide (15ml).

After two hours, the dicyclohexylurea is filtered out and the solutionis diluted with water (150 ml) and extracted with ethylether. Theorganic phases are collected and, after the usual work-up, the rsidualoil is purified by chromatography on SiO₂ (hexane-AcOEt 1:1) to give 1.8g of 3-(phenylthioacetyl)-2-(hydroxyphenoxy)methyl-thiazolidine m.p.94°-96° C.

In similar way, the following derivatives are prepared:

3-(phenylthioacetyl)-2-(O-methoxyphenoxy)methyl-thiazolidine, m.p.97°-99° C.;

3-(3-thia-pentanoyl)-2-(O-methoxyphenoxy)methyl-thiazolidine, m.p.66°-67° C.

EXAMPLE 51

A solution of 1-acetylcysteine disodium salt (638 mg) in MeOH (3 ml) istreated with a solution of3-(α-chloroacetyl)-2-(O-methoxyphenoxy)methyl-thiazolidine (0.88 g) indimethoxyethane (10 ml). After 2 hours at room temperature the mixtureis evaporated to dryness and the residue is partitioned between ethylacetate and aqueous 20% NaH₂ PO₄ solution.

The organic phase, after the usual work-up, gives 0.76 g of3-(5-carboxy-5-acetylamino-3-thia-pentanoyl)-2-(O-methoxyphenoxy)methyl-thiazolidine,m.p. 69°-78° C.

EXAMPLE 52

α-Methoxy-acetylchloride (7.3 ml) is added to a stirred solution of 14.8g of 2-(O-methoxyphenoxy)methyl-thiazolidine and triethylamine (11.2 ml)in sym-dichloroethane (100 ml), cooled at 0°-5° C. After 1 hour, themixture is washed with water. After the usual work-up andcrystallization from isopropanol, 11.46 g of3-(α-methoxyacetyl)-2-(O-methoxyphenoxy)methyl-thiazolidine, m.p.76°-77° C., are obtained.

Using in the same procedure the 3,6-dioxa-capriloyl-chloride and the3-thia-6-oxacapriloyl chloride, the following compounds are obtained:

3-(3,6-dioxa-capriloyl)-2-(O-methoxyphenoxy)methyl-thiazolidine, oil,H--NMR (CDCl₃ --THMS); 1.3 (3H, t, CH₂ --CH₃); 3.7 (6H, m, --O--CH₂--CH₂ --O--CH₂); 3.8 (3H, s, O--CH₃); 6.5 (4H, s)

3-(3-thia-6-oxa-capriloyl)-2-(O-methoxyphenoxy)methyl-thiazolidine, oil,H--NMR (CDCl₃ --THMS): 1.3 (3H, t, CH₂ CH₃); 3.82 (3H, s, OCH₃).

EXAMPLE 53

N,N'-Dicyclohexylcarbodiimide (22.7 g) is added to a stirred solution of2-(O-methoxyphenoxy)methyl-thiazolidine (22.6 g), N-acetylglycine (12.9g) and 4-dimethylaminopyridine (1.08 g) in sym-dichloroethane cooled at0° C. After 12 hours, the dicyclohexylurea is removed by filtration, andthe organic phase is washed with 5% aqueous NaHCO₃, water and then it isdried on Na₂ SO₄. After removal of solvents in vacuum, the residual oilis crystallized from isopropanol to give3-(N-acetylaminoacetyl)-2-(O-methoxyphenoxy)methyl-thiazolidine, m.p.119°-120° C. Using in this procedure BOC-glycine and N-formylglycine,the corresponding3-(N-formylaminoacetyl)-2-(O-methoxyphenoxy)methyl-thiazolidine, m.p.104°-106° C., 3-(BOC-glycinyl)-2-(O-methoxyphenoxy)methyl-thiazolidineoil, are prepared.

By treatment of the BOC-derivative with trifluoroacetic acid andmethylene chloride at room temperature, using the procedure of theExample 2, the 3-(glycinyl) compound is prepared.

By treatment of a solution of the N-formyl-glycinyl compound (15.07 g)in methanol (250 ml) with an 8N HCl solution in isopropanol (9 ml) for 8hours at room temperature, followed by concentration of the mixture atvolume of 50 ml and filtration, 12 g of

3-glycinyl-2-(O-methoxyphenoxy)methyl-thiazolidine.HCl m.p. 182°184° C.,are obtained.

EXAMPLE 54

A stirred solution of 3,5-dibromo-salicylaldehyde (8.37 g),3-glycinyl-2-(O-methoxyphenoxy)methyl-thiazolidine-hydrochloride (9.54g) and triethylamine (4.14 ml) in methanol (250 ml) is heated at refluxtemperature for 3 hours and then cooled to room temperature. Stirring incontinued for 8 hours to precipitate 15.12 g of3-(2-(3,5-dibromo-2-hydroxy-benzylidenamino-acetyl)-2-(O-methoxyphenoxy)methyl-thiazolidine,m.p. 126°-130° C.

10% NaBH₄ on alumina (11.8 g) is added to a stirred solution of thiscompound in ethylacetate (250 ml). After 6 hours, the organic phase isfiltered, washed with water and dried on Na₂ SO₄.

After treatment with 8N HCl in isopropanol (4.8 ml),3-(3',5'-dibromo-6'-hydroxyphenyl)methylaminoacetyl-2-(O-methoxyphenoxy)methyl-thiazolidine-hydrochloride(12.2 g), m.p. 193°-196° C., is obtained.

The following examples illustrate various unit dosage compositionscontaining a compound of the present invention as the active ingredient.

In case of diabetic patients, sorbitol can be used instead ofsaccharose.

EXAMPLE 55

    ______________________________________                                        3-Acetylthioacetyl-2-(o-methoxyphenoxy)-                                      methyl-thiazolidine      g      0.50                                          Polysorbitan monooleate  g      0.05                                          Sodium carboxymethylcellulose                                                                          g      0.30                                          Mycrocrystalline cellulose                                                                             g      0.70                                          Citric acid              g      0.1                                           Sodium citrate           g      0.8                                           Sodium benzoate          g      0.12                                          Methyl p-hydroxybenzoate g      0.035                                         Propyl p-hydroxybenzoate g      0.015                                         Aroma                    q.s.                                                 Sorbitol 70%             g      20                                            Saccharose               g      30                                            Water to                 ml     100.                                          ______________________________________                                    

EXAMPLE 56

    ______________________________________                                        3-(3,4,5-Trimethoxy)benzoylthioacetyl-2-(o-                                   methoxyphenoxy)methyl-thiazolidine                                                                     g      2.5                                           Polyethylenglycol        g      45                                            Ethanol 95 to            ml     100.                                          ______________________________________                                    

EXAMPLE 57

    ______________________________________                                        3-(4'-Methylpyperazin-1-yl)acetyl-2-(o-methoxy-                               phenoxy)methyl-thiazolidine dihydrochloride                                                             g      0.61                                         Saccharose                g      50                                           Sodium benzoate           g      0.12                                         Methyl-p-hydroxybenzoate  g      0.035                                        Propyl-p-hydroxybenzoate  g      0.015                                        Aroma                     q.s.                                                Water to                  ml     100.                                         ______________________________________                                    

EXAMPLE 58

    ______________________________________                                        3α-Acetylthioacetyl-2-(o-methoxyphenylthio)-                            methyl-4-carboxy-thiazolidine tromethamine salt                                                        g       0.653                                        Saccharose               g       50                                           Sodium benzoate          g       0.12                                         Methyl-p-hydroxybenzoate g       0.035                                        Propyl-p-hydroxybenzoate g       0.015                                        Tromethamine             g       0.303                                        HCl                      g       0.053                                        Aroma                    q.b.                                                 Water to                 ml      100.                                         ______________________________________                                    

EXAMPLE 59

Using cysteine hydrochloride instead of cysteamine in the procedure ofthe Examples 4 and 7, the following compounds are obtained:

4-carboxy-2-[2'-(o-hydroxyphenyl)ethyl]-thiazolidine, m.p. 182°-183° C.;

4-carboxy-2-[(o-hydroxyphenoxy)methyl]-thiazolidine, m.p. 182°-183° C.

We claim:
 1. Compound of formula I ##STR36## wherein: X is a CH₂, O, S;Ris hydroxy, or an ester thereof of formula R_(c) --CO₂ --, lower C₁ -C₆-alkoxy, CH₂ ═CH--CH₂ O--; HC.tbd.C--CH₂ --O--; or methyl R₁ is hydrogenor ##STR37## p is zero or 1 with the proviso that when X is sulfur p iszero; both R_(a) and R_(b), are hydrogen or methyl; R₂ is hydrogen andR₃ is hydrogen, a C₁ -C₂ alkylsulphonyl group, an unsubstituted or monoor polysubstituted phenylsulfonyl group or an acyl group of formulaR_(d) CO--; Rc and Rd, which are the same or different are: hydrogen,--O--C(CH₃)₃, --(CH₂)_(n) --Q and ##STR38## wherein n is 0 or an integerfrom 1 to 7; P₁ and P₂ are both hydrogen or one of them is hydrogen andthe other one is lower C₁ -C₄ alkyl or phenyl and Q is selected from thegroup consisting of: hydrogen; a C₃ -C₄ -branched alkyl; a C₃ -C₇cycloalkyl; free or esterified carboxy group; a halogen atom; SH; --NH₂; a mono or disubstituted amino, t-butoxy carbonylamino or C₁ -C₂acylamino group; an ether --O--(CH₂)_(m) --T or thioether --S--T chain,wherein T is an unsubstituted or mono- or polysubstituted phenyl ring ora group of formula --(CH₂)_(m) --T₁, wherein T₁ is selected from thegroup consisting of H, OH, --OCH₃, --OC₂ H₅, HOCH₂ --CH₂ --, free oresterified carboxy group, --NH₂, a C₁ -C₂ -acylamino or mono ordisubstituted amino group, or a group of formula ##STR39## wherein R_(e)is hydrogen, methyl or ethyl and m is an integer from 1 to 3; a phenyl,phenoxy or phenylthio ring unsubstituted or mono- or polysubstituted inthe m, o, and p-positions; a group of formula --(CH₂)_(m)--SCO--(CH₂)_(n) P₃ wherein m and n have the above defined meanings andP₃ is a lower C₁ -C₇ linear or branched alkyl chain, a C₃ -C₆-cycloalkyl, a disubstituted amino group, a phenyl or phenoxy ring,optionally mono- or polysubstituted in the o, m and p-positions; analkenyl chain of formula ##STR40## wherein T, in addition to the abovedefined meanings, is also hydrogen; or R₂ is a free or esterifiedcarboxy group; and R₃ is hydrogen, a C₁ -C₂ alkylsulphonyl group, anunsubstituted or mono- or polysubstituted phenylsulfonyl group or anacyl group of formula R'_(d) CO--; wherein R'_(d) is hydrogen,--O--C(CH₃)₃, --(CH₂)_(n) --Q' and ##STR41## wherein n is 0 or aninteger from 1 to 7; P₁, P₂, are both hydrogen or one of them ishydrogen and the other one is lower C₁ -C₄ alkyl or phenyl and Q' isselected from the group consisting of: hydrogen; a C₃ -C₄ -branchedalkyl; a C₃ -C₇ cycloalkyl; free or esterified carboxy group; --NH₂ ; amono or disubstituted amino, t-butoxy carbonylamino or C₁ -C₂ acylaminogroup; an ether --O--(CH₂)_(m) --T or thioether--S--T chain, wherein Tis an unsubstituted or mono- or polysubstituted phenyl ring or a groupof formula --(CH₂)_(m) T₁, wherein T₁ is selected from the groupconsisting of H, OH, --OCH₃, --OC₂ H₅, HOCH₂ --CH₂ --, free andesterified carboxy group, NH₂, a C₁ --C₂ -acylamino or mono ordisubstituted amino group, or a group of formula ##STR42## wherein R_(e)is hydrogen, methyl or ethyl and m is an integer from 1 to 3; a phenyl,phenoxy or phenylthio ring unsubstituted or mono- or polysubstituted inthe m, o, and p-positions; wherein the term "mono substituted aminogroup" means an amino group substituted by a C₁ -C₆ linear or branchedalkyl group or by groups having the formula:

    --CH.sub.2 --CH.sub.2 --O--CH.sub.2 --CH.sub.3, --CH.sub.2 --CH.sub.2 --O--CH.sub.2 --CH.sub.2 --OH,

    --CH.sub.2 --CH.sub.2 --NH--CH.sub.2 --CH.sub.3, --CH.sub.2 --CH.sub.2 --NH--CH.sub.2 --CH.sub.2 --OH or ##STR43##  wherein the substituents of a disubstituted amino group are linear or branched C.sub.1 -C.sub.6 alkyl groups or, taken together, are an unsaturated or saturated nitrogen containing ring selected from the group consisting of:

morpholin-1-yl, pyrrolidin-1-yl, piperidin-1-yl,4-methyl-piperazin-1-yl, 4-ethyl-piperazin-1-yl,4-(2'-hydroxyethyl)piperazin-1-yl, 4-phenyl-piperazin-1-yl,4-(3'chlorophenyl)piperazin-1-yl, 4-(4'-fluorophenyl)piperazin-1-yl;imidazol-1-yl, 3-pyridyl, 4-pyridyl; and wherein the term "mono- orpolysubstituted phenyl" means phenyl which is substituted by a fluorineatom in the para position, by chlorine atoms in the meta and/or parapositions, or by a CF₃ group in the meta position, or a phenyl group ofthe formula ##STR44## wherein Z₁ is H or --COCH₃ or --COCH₃ and Z₂ is H,CH₃ or COCH₃ and P₄ is hydrogen, aminomethyl, C₁ -C₂ -acylaminomethyl ora mono or disubstituted aminomethyl group, as above defined; provided,however, that said compound contains, at least one disubstituted aminogroup having the substituents thereof being said unsaturated orsaturated nitrogen-containing ring; or salts with non-toxic bases oracids thereof, enantiomers, diastereoisomers or mixtures thereof.
 2. Apharmaceutical composition having mucus regulating, bronchodilatoryand/or antitussive activity containing a therapeutically effectiveamount of a compound as claimed in claim 1, in admixture with anon-toxic carrier or excipient.
 3. Compound of claim 1 wherein saidcompound is2-(O-methoxyphenoxy)methyl-3-(4'-methyl-pyrazin-1-yl)-acetylthiazolidineor the hydrochloride salt thereof.
 4. Compoound of claim 1 wherein saidcompound is2-(O-methoxyphenoxy)methyl-3-(4-methyl-pyrazin-1-yl)-acetylthioacetyl-thiazolidineor the bis hydrochloride salt thereof.
 5. Compound of claim 1 whereinsaid compound is2-(O-hydroxyphenoxy)methyl-3-imidazol-1'-yl-acetyl-thiazolidine or themethyl or ethylether thereof, said ethylether being in the form of thefree base, or the hydrochloride or nitrate salt.
 6. Compound of claim 1wherein said compound is2-(O-methoxyphenoxy)methyl-3-imidazol-1-yl-acetyl-thioacetyl-thiazolidine,the form of the free base or the nitrate salt thereof.
 7. Compound ofclaim 1 wherein said compound is2-(O-methoxyphenylthio)methyl-3-(4'-methylpiperazin-1-'-yl)-acetylthioacetyl-thiazolidine.8. Compound of claim 1 wherein said compound is2-(O-methoxyphenylthio)methyl-3(4'-methylpiperazin-1'-yl)acetyl-thiazolidine, as the free base or the dihydrochloride salt. 9.Compound of claim 1 wherein said compound is2-[2'-(O-methoxyphenyl)ethyl]-3-(4'methyl-pyrazin-1-yl)acetyl-thiazolidine10. Compound of claim 1 wherein said compound is2-[2'(O-methoxyphenyl)ethyl]-3-piperidin-1-yl-acetyl-thiazolidine. 11.Compound of claim 1 wherein said compound is2-(O-methoxyphenoxy)methyl-3-piperidin-1-yl-acetyl-thiazolidine. 12.Compound of claim 1 wherein said compound is2-(O-methoxyphenylthio)methyl-3-piperidin-1-yl-acetyl-thiazolidine. 13.Compound of claim 1 wherein said compound is3-(3'morpholinomethyl-4'hydroxy-3'methoxy-cinnamoyl)-2-(O-methoxyphenoxy)-methyl-thiazolidine.14. Compound of claim 1 wherein said compound is3-(3'-pyrrolidylmethyl-4'-hydroxy-3'methoxy-cinnamoyl)-2-(O-hydroxyphenoxy)-methylthiazolidine.